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Myocardial Cell Signaling During the Transition to Heart Failure

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ABSTRACT

Cardiovascular disease leading to heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Improved pharmacological and interventional coronary procedures have led to improved outcomes following acute myocardial infarction. This success has translated into an unforeseen increased incidence in HF. This review summarizes the signaling pathways implicated in the transition to HF following cardiac injury. In addition, we provide an update on cell death signaling and discuss recent advances in cardiac fibrosis as an independent event leading to HF. Finally, we discuss cell‐based therapies and their possible use to avert the deteriorating nature of HF. © 2019 American Physiological Society. Compr Physiol 9:75‐125, 2019.

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Figure 1. Figure 1. A‐B, longitudinal (A) and transverse (B) section of the normal/healthy heart. C‐D, longitudinal (C) and transverse (D) section of the remodeled heart. A, atrium; LV, left ventricle; RV; right ventricle.
Figure 2. Figure 2. Molecular pathway of cardiac remodeling.
Figure 3. Figure 3. β1 and β2 AR coupling and signal transduction in cardiac myocytes. β2 AR acts on cell survival signals through Gs‐cAMP‐PKA‐Akt and Gi‐PI3K‐AktGβγ pathways. In contrast, β1 AR binds to Gs, which activates PKA‐independent, CamKII‐mediated apoptotic pathway. ECC, excitation‐contraction coupling.
Figure 4. Figure 4. G‐protein‐mediated signal transduction. Agonist binds to the receptor, which leads to the exchange of G‐protein‐bound GDP for GTP. Gα and Gβγ subunits are dissociated from the activated form of G‐protein. Gα is classified into four subclasses, including Gαs, Gαi, Gαq, and Gα12. Gαs is a stimulatory member, which binds to adenylyl cyclase (AC) and increases intracellular cAMP levels. Gαi is an inhibitory member which decreases cAMP levels. Gαq activates PLC‐β, whereas Gα12 acts on Rac and Rho. Gβγ dimers activate ion channels, MAP (mitogen‐activated protein) kinase and activate or inhibit AC.
Figure 5. Figure 5. Adrenergic receptors in human cardiac tissue. These receptors bind to the two effector pathways in human myocyte. AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DG, diacylglycerol; GDP, guanine diphosphate; GTP, guanosine triphosphate; IP3, inositol triphosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PLC, phospholipase C.
Figure 6. Figure 6. Mechanisms of pathological changes caused by ROS in the heart. ROS induces three different pathways, including PKC and PKB, MAPK, and TNFα.
Figure 7. Figure 7. Phases of myocardial wound healing post‐MI in patients. Depicted are the four phases of myocardial wound healing that occur following a myocardial infarction (MI). Note the overlapping time courses between inflammation, formation of granulation tissue, and scar formation phases.
Figure 8. Figure 8. TGFβ1/Smad‐independent signaling: p38 MAPK. In addition to its role in stimulating a Smad‐dependent pathway, extracellular TGFβ1 can stimulate a Smad‐independent pathway through TβRs. TGFβ1 promotes ubiquitination of TRAF6 (B), which in turn phosphorylates and forms a complex with TAK1. This activated complex induces phosphorylation of MKK3/6, which activates p38 kinase through phosphorylation. Activated p38 then has the capability to phosphorylate downstream transcription factors such as ATF2, CHOP, and CREB or the linker region of R‐Smad proteins to regulate their function. TGFβ1 also promotes phosphorylation of PI3K (C), which in turn phosphorylates Akt and PAK2. Signaling through the Akt pathway leads to cell migration, whereas signaling through a PAK2 dependent pathway leads to morphological transformation and cell proliferation. Actin organization, stabilization, and stress fiber formation are potently regulated by TGFβ1 signaling through a Smad‐independent pathway. Activation of TβRI promotes the activation of RhoA (D). RhoA can then induce the activity of both mDia and ROCK by phosphorylation. ROCK activation leads to phosphorylation of MRTF and the formation of a complex with SRF. Additionally, ROCK stimulates LIMK, which represses cofilin. Collectively, these pathways lead to actin cytoskeleton organization, F‐actin stabilization, and stress fiber formation. In addition, ERK1/2 (A) is a well‐described TGFβ1 triggered signal pathway that is Smad independent. TGFβ1 stimulation of its receptors leads to the phosphorylation of the adaptor protein Shc. Active Shc forms a complex with Grb2 and SOS, which is capable of promoting activation of Ras. Activation of Ras leads to a MAPK signaling cascade, which ultimately leads to phosphorylation of ERK1/2 through MEK1/2. Erk1/2 can then phosphorylate transcription factors, such as Elk1, to modify gene expression.
Figure 9. Figure 9. Protein structure of Ski. The human Ski protein is depicted earlier. At the NH2 end of the protein lies a DHD, that plays a critical role in protein‐protein interactions, and an R‐Smad2/3 interacting domain that is important for Ski's ability to repress TGFβ/Smad‐dependent signaling. Slightly further downstream lies the unique C2H2 (SAND) domain that regulates the interaction of Ski with Co‐Smad4. The COOH end of the protein is less conserved than that of the NH2 end. However, the COOH terminal plays an important role in Ski:Sno homo‐ and hetero‐dimerization as well as nuclear translocation of Ski [PRKRKLT—nuclear localization signal (NLS)].
Figure 10. Figure 10. Ski‐mediated repression of TGFβ1/Smad signaling. (A) Ski is primarily a nuclear protein. Within the nucleus, Ski can inhibit Smad dependent signaling by forming an inhibitory complex with the R‐Smad/Co‐Smad complex and stabilize them while bound to DNA. Ski then recruits a transcriptional inhibitory complex that includes NCoR, mSin3a, and HDACs to inhibit gene transcription. Ski can also be found within the cytoplasmic fraction of cells. Although its function has been extensively described in the nucleus, Ski can repress TGFβ1/Smad signaling from the cytoplasm in two ways. First, (B) Ski can form a complex with the Smad complex and prevent nuclear translocation. Second, (C) Ski can prevent R‐Smad phosphorylation at the level of the TβRI and prevent R‐Smad complex formation at the initiating step.
Figure 11. Figure 11. Schematic of the reciprocal hypothesis. Ski and Scx form a negative feedback loop that regulates their gene expression. In the chronic post‐MI setting, we believe that this balance is tipped in favor of Scx, which promotes repression of Ski transcription leading to remodeling of the cardiac matrix. With TGFβ1 signaling unchecked by Ski, there is a significant increase in expression of fibrillar collagens and matrix proteins that ultimately cumulate to interstitial fibrosis and HF.
Figure 12. Figure 12. Proposed mechanism for the regulation of Scx by p44/42 (ERK1/2) and Ski. TGFβ1 is a powerful inducer of Scx expression. We have demonstrated that TGFβ1 may exert its effects on Scx expression through a TGFβ1/Smad‐independent mechanism that includes the p44/42 MAPK signaling pathway in combination with c‐Jun activation in cardiac myofibroblasts. As we did not completely restore abrogated Scx protein expression with the MEK1/2 inhibitor U0126, Smad proteins may still be involved in regulating Scx through an alternative mechanism that has yet to be described. We have shown Ski to be a potent inhibitor of Scx signaling and we propose that Ski exerts its effects through inhibition of p44/42 in addition to its role in preventing Smad‐mediated gene regulation.
Figure 13. Figure 13. Application of naturally derived and synthetic biomaterials in cardiovascular tissue engineering. (A) Representative images from highly elastic scaffold made from the methacrylate form of tropoelastin (MeTro) before and after stretching. Extensible MeTro molecule with an asymmetric coil and a C‐terminal cell interactive motif. (B) Images of MeTro‐based hydrogels under torsion test before (left) and after 27 rotations (right). (C) No breakage in the hydrogel structure was observed after twisting. Reprinted with permission from (18). Copyright 2015, WILEY‐VCH Verlag GmbH & Co. (D) Fluorescent images of cardiac fibroblasts cultured on random and aligned electrospun scaffolds made from gelatin:PGS blend. Cells were stained for α‐SMA (red), F‐actin (green), and DAPI (blue) after 5 days of culture. Reprinted with permission from (258). Copyright 2013, Elsevier.


Figure 1. A‐B, longitudinal (A) and transverse (B) section of the normal/healthy heart. C‐D, longitudinal (C) and transverse (D) section of the remodeled heart. A, atrium; LV, left ventricle; RV; right ventricle.


Figure 2. Molecular pathway of cardiac remodeling.


Figure 3. β1 and β2 AR coupling and signal transduction in cardiac myocytes. β2 AR acts on cell survival signals through Gs‐cAMP‐PKA‐Akt and Gi‐PI3K‐AktGβγ pathways. In contrast, β1 AR binds to Gs, which activates PKA‐independent, CamKII‐mediated apoptotic pathway. ECC, excitation‐contraction coupling.


Figure 4. G‐protein‐mediated signal transduction. Agonist binds to the receptor, which leads to the exchange of G‐protein‐bound GDP for GTP. Gα and Gβγ subunits are dissociated from the activated form of G‐protein. Gα is classified into four subclasses, including Gαs, Gαi, Gαq, and Gα12. Gαs is a stimulatory member, which binds to adenylyl cyclase (AC) and increases intracellular cAMP levels. Gαi is an inhibitory member which decreases cAMP levels. Gαq activates PLC‐β, whereas Gα12 acts on Rac and Rho. Gβγ dimers activate ion channels, MAP (mitogen‐activated protein) kinase and activate or inhibit AC.


Figure 5. Adrenergic receptors in human cardiac tissue. These receptors bind to the two effector pathways in human myocyte. AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DG, diacylglycerol; GDP, guanine diphosphate; GTP, guanosine triphosphate; IP3, inositol triphosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PLC, phospholipase C.


Figure 6. Mechanisms of pathological changes caused by ROS in the heart. ROS induces three different pathways, including PKC and PKB, MAPK, and TNFα.


Figure 7. Phases of myocardial wound healing post‐MI in patients. Depicted are the four phases of myocardial wound healing that occur following a myocardial infarction (MI). Note the overlapping time courses between inflammation, formation of granulation tissue, and scar formation phases.


Figure 8. TGFβ1/Smad‐independent signaling: p38 MAPK. In addition to its role in stimulating a Smad‐dependent pathway, extracellular TGFβ1 can stimulate a Smad‐independent pathway through TβRs. TGFβ1 promotes ubiquitination of TRAF6 (B), which in turn phosphorylates and forms a complex with TAK1. This activated complex induces phosphorylation of MKK3/6, which activates p38 kinase through phosphorylation. Activated p38 then has the capability to phosphorylate downstream transcription factors such as ATF2, CHOP, and CREB or the linker region of R‐Smad proteins to regulate their function. TGFβ1 also promotes phosphorylation of PI3K (C), which in turn phosphorylates Akt and PAK2. Signaling through the Akt pathway leads to cell migration, whereas signaling through a PAK2 dependent pathway leads to morphological transformation and cell proliferation. Actin organization, stabilization, and stress fiber formation are potently regulated by TGFβ1 signaling through a Smad‐independent pathway. Activation of TβRI promotes the activation of RhoA (D). RhoA can then induce the activity of both mDia and ROCK by phosphorylation. ROCK activation leads to phosphorylation of MRTF and the formation of a complex with SRF. Additionally, ROCK stimulates LIMK, which represses cofilin. Collectively, these pathways lead to actin cytoskeleton organization, F‐actin stabilization, and stress fiber formation. In addition, ERK1/2 (A) is a well‐described TGFβ1 triggered signal pathway that is Smad independent. TGFβ1 stimulation of its receptors leads to the phosphorylation of the adaptor protein Shc. Active Shc forms a complex with Grb2 and SOS, which is capable of promoting activation of Ras. Activation of Ras leads to a MAPK signaling cascade, which ultimately leads to phosphorylation of ERK1/2 through MEK1/2. Erk1/2 can then phosphorylate transcription factors, such as Elk1, to modify gene expression.


Figure 9. Protein structure of Ski. The human Ski protein is depicted earlier. At the NH2 end of the protein lies a DHD, that plays a critical role in protein‐protein interactions, and an R‐Smad2/3 interacting domain that is important for Ski's ability to repress TGFβ/Smad‐dependent signaling. Slightly further downstream lies the unique C2H2 (SAND) domain that regulates the interaction of Ski with Co‐Smad4. The COOH end of the protein is less conserved than that of the NH2 end. However, the COOH terminal plays an important role in Ski:Sno homo‐ and hetero‐dimerization as well as nuclear translocation of Ski [PRKRKLT—nuclear localization signal (NLS)].


Figure 10. Ski‐mediated repression of TGFβ1/Smad signaling. (A) Ski is primarily a nuclear protein. Within the nucleus, Ski can inhibit Smad dependent signaling by forming an inhibitory complex with the R‐Smad/Co‐Smad complex and stabilize them while bound to DNA. Ski then recruits a transcriptional inhibitory complex that includes NCoR, mSin3a, and HDACs to inhibit gene transcription. Ski can also be found within the cytoplasmic fraction of cells. Although its function has been extensively described in the nucleus, Ski can repress TGFβ1/Smad signaling from the cytoplasm in two ways. First, (B) Ski can form a complex with the Smad complex and prevent nuclear translocation. Second, (C) Ski can prevent R‐Smad phosphorylation at the level of the TβRI and prevent R‐Smad complex formation at the initiating step.


Figure 11. Schematic of the reciprocal hypothesis. Ski and Scx form a negative feedback loop that regulates their gene expression. In the chronic post‐MI setting, we believe that this balance is tipped in favor of Scx, which promotes repression of Ski transcription leading to remodeling of the cardiac matrix. With TGFβ1 signaling unchecked by Ski, there is a significant increase in expression of fibrillar collagens and matrix proteins that ultimately cumulate to interstitial fibrosis and HF.


Figure 12. Proposed mechanism for the regulation of Scx by p44/42 (ERK1/2) and Ski. TGFβ1 is a powerful inducer of Scx expression. We have demonstrated that TGFβ1 may exert its effects on Scx expression through a TGFβ1/Smad‐independent mechanism that includes the p44/42 MAPK signaling pathway in combination with c‐Jun activation in cardiac myofibroblasts. As we did not completely restore abrogated Scx protein expression with the MEK1/2 inhibitor U0126, Smad proteins may still be involved in regulating Scx through an alternative mechanism that has yet to be described. We have shown Ski to be a potent inhibitor of Scx signaling and we propose that Ski exerts its effects through inhibition of p44/42 in addition to its role in preventing Smad‐mediated gene regulation.


Figure 13. Application of naturally derived and synthetic biomaterials in cardiovascular tissue engineering. (A) Representative images from highly elastic scaffold made from the methacrylate form of tropoelastin (MeTro) before and after stretching. Extensible MeTro molecule with an asymmetric coil and a C‐terminal cell interactive motif. (B) Images of MeTro‐based hydrogels under torsion test before (left) and after 27 rotations (right). (C) No breakage in the hydrogel structure was observed after twisting. Reprinted with permission from (18). Copyright 2015, WILEY‐VCH Verlag GmbH & Co. (D) Fluorescent images of cardiac fibroblasts cultured on random and aligned electrospun scaffolds made from gelatin:PGS blend. Cells were stained for α‐SMA (red), F‐actin (green), and DAPI (blue) after 5 days of culture. Reprinted with permission from (258). Copyright 2013, Elsevier.
References
 1.World Health Statistics. Geneva, Switzerland: World Health Organization, 2013, p. 172.
 2.Afanas'ev I. ROS and RNS signaling in heart disorders: Could antioxidant treatment be successful? Oxid Med Cell Longev 2011: 293769, 2011.
 3.Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 106: 1253‐1264, 2010.
 4.Ahadian S, Yamada S, Ramon‐Azcon J, Estili M, Liang X, Nakajima K, Shiku H, Khademhosseini A, Matsue T. Hybrid hydrogel‐aligned carbon nanotube scaffolds to enhance cardiac differentiation of embryoid bodies. Acta Biomater 31: 134‐143, 2016.
 5.Ahn B, Beharry AW, Frye GS, Judge AR, Ferreira LF. NAD(P)H oxidase subunit p47phox is elevated, and p47phox knockout prevents diaphragm contractile dysfunction in heart failure. Am J Physiol Lung Cell Mol Physiol 309: L497‐L505, 2015.
 6.Akbari M, Tamayol A, Bagherifard S, Serex L, Mostafalu P, Faramarzi N, Mohammadi MH, Khademhosseini A. Textile technologies and tissue engineering: A path toward organ weaving. Adv Healthc Mater 5: 751‐766, 2016.
 7.Akhmedov AT, Marin‐Garcia J. Myocardial regeneration of the failing heart. Heart Fail Rev 18: 815‐833, 2013.
 8.Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, Kawabata M. c‐Ski acts as a transcriptional co‐repressor in transforming growth factor‐beta signaling through interaction with smads. J Biol Chem 274: 35269‐35277, 1999.
 9.Al‐khateeb M, Qureshi WT, Odeh R, Ahmed AM, Sakr S, Elshawi R, Bdeir MB, Al‐Mallah MH. The impact of digoxin on mortality in patients with chronic systolic heart failure: A propensity‐matched cohort study. Int J Cardiol 228: 214‐218, 2017.
 10.Alghamdi F, Chan M. Management of heart failure in the elderly. Curr Opin Cardiol 32(2): 217‐223, 2017. doi: 10.1097/HCO.0000000000000375.
 11.Almeida SO, Skelton RJ, Adigopula S, Ardehali R. Arrhythmia in stem cell transplantation. Card Electrophysiol Clin 7: 357‐370, 2015.
 12.Ambrosi P, Daumas A, Villani P, Giorgi R. Meta‐analysis of major bleeding events on aspirin versus vitamin K antagonists in randomized trials. Int J Cardiol 230: 572‐576, 2016.
 13.Ammar HI, Sequiera GL, Nashed MB, Ammar RI, Gabr HM, Elsayed HE, Sareen N, Rub EA, Zickri MB, Dhingra S. Comparison of adipose tissue‐ and bone marrow‐derived mesenchymal stem cells for alleviating doxorubicin‐induced cardiac dysfunction in diabetic rats. Stem Cell Res Ther 6: 148, 2015.
 14.Amsterdam EA, Venugopal S, Thinda A. Pathophysiology of acute decompensated heart failure. In: Short Stay Management of Acute Heart Failure. Springer Nature Switzerland: Springer, 2017, pp. 81‐88.
 15.Andersen S, Andersen A, Nielsen‐Kudsk JE. The renin‐angiotensin‐aldosterone‐system and right heart failure in congenital heart disease. Int J Cardiol Heart Vasc 11: 59‐65, 2016.
 16.Anderson RH, Yanni J, Boyett MR, Chandler NJ, Dobrzynski H. The anatomy of the cardiac conduction system. Clin Anat 22: 99‐113, 2009.
 17.Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 86: 123‐130, 2002.
 18.Annabi N, Shin SR, Tamayol A, Miscuglio M, Bakooshli MA, Assmann A, Mostafalu P, Sun JY, Mithieux S, Cheung L. Highly elastic and conductive human‐based protein hybrid hydrogels. Adv Mater 28: 40‐49, 2016.
 19.Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, Camci‐Unal G, Dokmeci MR, Peppas NA, Khademhosseini A. 25th anniversary article: Rational design and applications of hydrogels in regenerative medicine. Adv Mater 26: 85‐124, 2014.
 20.Annabi N, Tsang K, Mithieux SM, Nikkhah M, Ameri A, Khademhosseini A, Weiss AS. Highly elastic micropatterned hydrogel for engineering functional cardiac tissue. Adv Funct Mater 23: 4950‐4959, 2013.
 21.Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN. Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circ Res 89: 997‐1004, 2001.
 22.Arndt S, Poser I, Moser M, Bosserhoff AK. Fussel‐15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Mol Cell Neurosci 34: 603‐611, 2007.
 23.Arndt S, Poser I, Schubert T, Moser M, Bosserhoff AK. Cloning and functional characterization of a new Ski homolog, Fussel‐18, specifically expressed in neuronal tissues. Lab Invest 85: 1330‐1341, 2005.
 24.Arslan F, Smeets MB, O'Neill LA, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll‐like receptor‐2 and reduced by systemic administration of a novel anti‐toll‐like receptor‐2 antibody. Circulation 121: 80‐90, 2010.
 25.Arutyunyan I, Elchaninov A, Makarov A, Fatkhudinov T. Umbilical cord as prospective source for mesenchymal stem cell‐based therapy. Stem Cells Int 2016: 6901286, 2016.
 26.Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Phosphatidylinositol 3‐kinase is involved in alpha2(I) collagen gene expression in normal and scleroderma fibroblasts. J Immunol 172: 7123‐7135, 2004.
 27.Asou Y, Nifuji A, Tsuji K, Shinomiya K, Olson EN, Koopman P, Noda M. Coordinated expression of scleraxis and Sox9 genes during embryonic development of tendons and cartilage. J Orthop Res 20: 827‐833, 2002.
 28.Atfi A, Djelloul S, Chastre E, Davis R, Gespach C. Evidence for a role of Rho‐like GTPases and stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) in transforming growth factor beta‐mediated signaling. J Biol Chem 272: 1429‐1432, 1997.
 29.Au PY, Racher HE, Graham JM, Jr., Kramer N, Lowry RB, Parboosingh JS, Innes AM, Consortium FC. De novo exon 1 missense mutations of SKI and Shprintzen‐Goldberg syndrome: Two new cases and a clinical review. Am J Med Genet A 164A: 676‐684, 2014.
 30.Azzawi M, Hasleton P. Tumour necrosis factor alpha and the cardiovascular system: Its role in cardiac allograft rejection and heart disease. Cardiovasc Res 43: 850‐859, 1999.
 31.Backs J, Backs T, Bezprozvannaya S, McKinsey TA, Olson EN. Histone deacetylase 5 acquires calcium/calmodulin‐dependent kinase II responsiveness by oligomerization with histone deacetylase 4. Mol Cell Biol 28: 3437‐3445, 2008.
 32.Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest 116: 1853‐1864, 2006.
 33.Badie N, Satterwhite L, Bursac N. A method to replicate the microstructure of heart tissue in vitro using DTMRI‐based cell micropatterning. Ann Biomed Eng 37: 2510‐2521, 2009.
 34.Bagchi RA, Czubryt MP. Synergistic roles of scleraxis and Smads in the regulation of collagen 1alpha2 gene expression. Biochim Biophys Acta 1823: 1936‐1944, 2012.
 35.Bagchi RA, Wang R, Jahan F, Wigle JT, Czubryt MP. Regulation of scleraxis transcriptional activity by serine phosphorylation. J Mol Cell Cardiol 92: 140‐148, 2016.
 36.Baggen VJ, Eindhoven JA, van den Bosch AE, Witsenburg M, Cuypers JA, Langstraat JS, Boersma E, Roos‐Hesselink JW. Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease. Biomarkers 21: 466‐473, 2016.
 37.Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658‐662, 2005.
 38.Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen‐activated protein kinase is required for TGFbeta‐mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 115: 3193‐3206, 2002.
 39.Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3‐kinase function is required for transforming growth factor beta‐mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 275: 36803‐36810, 2000.
 40.Balligand JL. Regulation of cardiac beta‐adrenergic response by nitric oxide. Cardiovasc Res 43: 607‐620, 1999.
 41.Band AM, Bjorklund M, Laiho M. The phosphatidylinositol 3‐kinase/Akt pathway regulates transforming growth factor‐{beta} signaling by destabilizing ski and inducing Smad7. J Biol Chem 284: 35441‐35449, 2009.
 42.Banerjee I, Fuseler JW, Price RL, Borg TK, Baudino TA. Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Physiol Heart Circ Physiol 293: H1883‐H1891, 2007.
 43.Banerjee I, Yekkala K, Borg TK, Baudino TA. Dynamic interactions between myocytes, fibroblasts, and extracellular matrix. Ann N Y Acad Sci 1080: 76‐84, 2006.
 44.Barnette DN, Hulin A, Ahmed AS, Colige AC, Azhar M, Lincoln J. Tgfbeta‐Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves. J Mol Cell Cardiol 65: 137‐146, 2013.
 45.Barsby T, Guest D. Transforming growth factor beta3 promotes tendon differentiation of equine embryo‐derived stem cells. Tissue Eng Part A 19: 2156‐2165, 2013.
 46.Baum J, Duffy HS. Fibroblasts and myofibroblasts: What are we talking about? J Cardiovasc Pharmacol 57: 376‐379, 2011.
 47.Bax NA, Pijnappels DA, van Oorschot AA, Winter EM, de Vries AA, van Tuyn J, Braun J, Maas S, Schalij MJ, Atsma DE, Goumans MJ, Gittenberger‐de Groot AC. Epithelial‐to‐mesenchymal transformation alters electrical conductivity of human epicardial cells. J Cell Mol Med 15: 2675‐2683, 2011.
 48.Bax NA, van Oorschot AA, Maas S, Braun J, van Tuyn J, de Vries AA, Groot AC, Goumans MJ. In vitro epithelial‐to‐mesenchymal transformation in human adult epicardial cells is regulated by TGFbeta‐signaling and WT1. Basic Res Cardiol 106: 829‐847, 2011.
 49.Bayless KJ, Salazar R, Davis GE. RGD‐dependent vacuolation and lumen formation observed during endothelial cell morphogenesis in three‐dimensional fibrin matrices involves the alpha(v)beta(3) and alpha(5)beta(1) integrins. Am J Pathol 156: 1673‐1683, 2000.
 50.Beber AR, Polina ER, Biolo A, Santos BL, Gomes DC, La Porta VL, Olsen V, Clausell N, Rohde LE, Santos KG. Matrix metalloproteinase‐2 polymorphisms in chronic heart failure: Relationship with susceptibility and long‐term survival. PLoS One 11: e0161666, 2016.
 51.Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of a gp91(phox)‐containing NADPH oxidase in angiotensin II‐induced cardiac hypertrophy in mice. Circulation 105: 293‐296, 2002.
 52.Benito B, Guasch E, Rivard L, Nattel S. Clinical and mechanistic issues in early repolarization of normal variants and lethal arrhythmia syndromes. J Am Coll Cardiol 56: 1177‐1186, 2010.
 53.Berk M, Desai SY, Heyman HC, Colmenares C. Mice lacking the ski proto‐oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development. Genes Dev 11: 2029‐2039, 1997.
 54.Bhana B, Iyer RK, Chen WLK, Zhao R, Sider KL, Likhitpanichkul M, Simmons CA, Radisic M. Influence of substrate stiffness on the phenotype of heart cells. Biotechnol Bioeng 105: 1148‐1160, 2010.
 55.Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. Transforming growth factor‐beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA‐dependent mechanism. Mol Biol Cell 12: 27‐36, 2001.
 56.Bianchi ME. HMGB1 loves company. J Leukoc Biol 86: 573‐576, 2009.
 57.Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J 5: 9‐19, 2012.
 58.Bishop JE, Greenbaum R, Gibson DG, Yacoub M, Laurent GJ. Enhanced deposition of predominantly type I collagen in myocardial disease. J Mol Cell Cardiol 22: 1157‐1165, 1990.
 59.Block D, Brunner H‐P, Wienhues‐Thelen U‐H, Zaugg C, Dieterle T, Mitchell C, Ubby J, Sanders‐van Wijk S. Biomarkers for risk assessment and treatment monitoring in heart failure patients guided by natriuretic peptides. Google Patents, 2016.
 60.Boffito M, Sartori S, Ciardelli G. Polymeric scaffolds for cardiac tissue engineering: Requirements and fabrication technologies. Polym Int 63: 2‐11, 2014.
 61.Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79: 609‐634, 1999.
 62.Borg TK, Caulfield JB. Collagen in the heart. Tex Rep Biol Med 39: 321‐333, 1979.
 63.Boyden PA, Hirose M, Dun W. Cardiac Purkinje cells. Heart Rhythm 7: 127‐135, 2010.
 64.Brassart B, Randoux A, Hornebeck W, Emonard H. Regulation of matrix metalloproteinase‐2 (gelatinase A, MMP‐2), membrane‐type matrix metalloproteinase‐1 (MT1‐MMP) and tissue inhibitor of metalloproteinases‐2 (TIMP‐2) expression by elastin‐derived peptides in human HT‐1080 fibrosarcoma cell line. Clin Exp Metastasis 16: 489‐500, 1998.
 65.Braunwald E. Heart failure. JACC Heart Fail 1: 1‐20, 2013.
 66.Brown D, Wagner D, Li X, Richardson JA, Olson EN. Dual role of the basic helix‐loop‐helix transcription factor scleraxis in mesoderm formation and chondrogenesis during mouse embryogenesis. Development 126: 4317‐4329, 1999.
 67.Bruce D, Pathmanathan P, Whiteley JP. Modelling the effect of gap junctions on tissue‐level cardiac electrophysiology. Bull Math Biol 76: 431‐454, 2014.
 68.Bruusgaard JC, Brack AS, Hughes SM, Gundersen K. Muscle hypertrophy induced by the Ski protein: Cyto‐architecture and ultrastructure. Acta Physiol Scand 185: 141‐149, 2005.
 69.Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1: 71‐81, 1994.
 70.Buess M, Terracciano L, Reuter J, Ballabeni P, Boulay JL, Laffer U, Metzger U, Herrmann R, Rochlitz C. Amplification of SKI is a prognostic marker in early colorectal cancer. Neoplasia 6: 207‐212, 2004.
 71.Bujak M, Frangogiannis NG. The role of TGF‐beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74: 184‐195, 2007.
 72.Burdick JA, Prestwic GD. Hyaluronic acid hydrogels for biomedical applications. Adv Healthc Mater 23 H41‐H56, 2011.
 73.Burnett H, Earley A, Voors AA, Senni M, McMurray JJ, Deschaseaux C, Cope S. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: A network meta‐analysis. Circ Heart Fail 10: 2017.
 74.Bursac N, Papadaki M, Cohen RJ, Schoen FJ, Eisenberg SR, Carrier R, Vunjak‐Novakovic G, Freed LE. Cardiac muscle tissue engineering: Toward an in vitro model for electrophysiological studies. Am J Physiol Heart Circ Physiol 277: H433‐H444, 1999.
 75.Byrne JA, Grieve DJ, Bendall JK, Li JM, Gove C, Lambeth JD, Cave AC, Shah AM. Contrasting roles of NADPH oxidase isoforms in pressure‐overload versus angiotensin II‐induced cardiac hypertrophy. Circ Res 93: 802‐805, 2003.
 76.Camci‐Unal G, Annabi N, Dokmeci MR, Liao R, Khademhosseini A. Hydrogels for cardiac tissue engineering. NPG Asia Mater 6: e99, 2014.
 77.Camelliti P, Borg TK, Kohl P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65: 40‐51, 2005.
 78.Camelliti P, Devlin GP, Matthews KG, Kohl P, Green CR. Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction. Cardiovasc Res 62: 415‐425, 2004.
 79.Camelliti P, McCulloch AD, Kohl P. Microstructured cocultures of cardiac myocytes and fibroblasts: A two‐dimensional in vitro model of cardiac tissue. Microsc Microanal 11: 249‐259, 2005.
 80.Canada PHAo. Tracking Heart Disease & Stroke in Canada. Edited by Wielgosz DA, Arango MM, Bancej DC, Bienek MA, Johansen DH, Lindsay DP, Luo MW, Luteyn MA, Nair MC, Quan MP, Stewart DP, Walsh MP, and Webster MGHealth Canada, 2009, p. 132.
 81.Canada S. Mortality, Summary, List of Causes ‐ 2006. 2010. https://www150.statcan.gc.ca/n1/pub/84209x/84209x2006000‐eng.htm.
 82.Canada S. Causes of Death, 2010 and 2011. 2014. https://www150.statcan.gc.ca/n1/daily‐quotidien/140128/dq140128b‐eng.htm.
 83.Canada S. Trends in Mortality Rates, 2000 to 2011. 2015. https://www150.statcan.gc.ca/n1/pub/82‐625‐x/2014001/article/11897‐eng.htm.
 84.Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E. Role of HIF‐1alpha in hypoxia‐mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394: 485‐490, 1998.
 85.Carmignac V, Thevenon J, Ades L, Callewaert B, Julia S, Thauvin‐Robinet C, Gueneau L, Courcet JB, Lopez E, Holman K, Renard M, Plauchu H, Plessis G, De Backer J, Child A, Arno G, Duplomb L, Callier P, Aral B, Vabres P, Gigot N, Arbustini E, Grasso M, Robinson PN, Goizet C, Baumann C, Di Rocco M, Sanchez Del Pozo J, Huet F, Jondeau G, Collod‐Beroud G, Beroud C, Amiel J, Cormier‐Daire V, Riviere JB, Boileau C, De Paepe A, Faivre L. In‐frame mutations in exon 1 of SKI cause dominant Shprintzen‐Goldberg syndrome. Am J Hum Genet 91: 950‐957, 2012.
 86.Carnegie GK, Smith FD, McConnachie G, Langeberg LK, Scott JD. AKAP‐Lbc nucleates a protein kinase D activation scaffold. Mol Cell 15: 889‐899, 2004.
 87.Carnegie GK, Soughayer J, Smith FD, Pedroja BS, Zhang F, Diviani D, Bristow MR, Kunkel MT, Newton AC, Langeberg LK, Scott JD. AKAP‐Lbc mobilizes a cardiac hypertrophy signaling pathway. Mol Cell 32: 169‐179, 2008.
 88.Castella LF, Buscemi L, Godbout C, Meister JJ, Hinz B. A new lock‐step mechanism of matrix remodelling based on subcellular contractile events. J Cell Sci 123: 1751‐1760, 2010.
 89.Castellano E, Downward J. RAS interaction with PI3K: More than just another effector pathway. Genes Cancer 2: 261‐274, 2011.
 90.Caulfield JB, Borg TK. The collagen network of the heart. Lab Invest 40: 364‐372, 1979.
 91.Chang CW, Dalgliesh AJ, López JE, Griffiths LG. Cardiac extracellular matrix proteomics: Challenges, techniques, and clinical implications. Proteomics Clin Appl 10: 39‐50, 2016.
 92.Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A 99: 12877‐12882, 2002.
 93.Chang L, Yang R, Wang M, Liu J, Wang Y, Zhang H, Li Y. Angiotensin II type‐1 receptor‐JAK/STAT pathway mediates the induction of visfatin in angiotensin II‐induced cardiomyocyte hypertrophy. Am J Med Sci 343: 220‐226, 2012.
 94.Chatelier A, Mercier A, Tremblier B, Theriault O, Moubarak M, Benamer N, Corbi P, Bois P, Chahine M, Faivre JF. A distinct de novo expression of Nav1.5 sodium channels in human atrial fibroblasts differentiated into myofibroblasts. J Physiol 590: 4307‐4319, 2012.
 95.Chavey WE, Hogikyan RV, van Harrison R, Nicklas JM. Heart failure due to reduced ejection fraction: Medical management. Am Fam Physician 95: 13‐20, 2017.
 96.Chello M, Mastroroberto P, Romano R, Zofrea S, Bevacqua I, Marchese AR. Changes in the proportion of types I and III collagen in the left ventricular wall of patients with post‐irradiative pericarditis. Cardiovasc Surg 4: 222‐226, 1996.
 97.Chen W, Frangogiannis NG. Fibroblasts in post‐infarction inflammation and cardiac repair. Biochim Biophys Acta 1833: 945‐953, 2013.
 98.Chen Y, Lewis W, Diwan A, Cheng EH, Matkovich SJ, Dorn GW, II. Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. Proc Natl Acad Sci U S A 107: 9035‐9042, 2010.
 99.Chester AH, Taylor PM. Molecular and functional characteristics of heart‐valve interstitial cells. Philos Trans R Soc Lond B Biol Sci 362: 1437‐1443, 2007.
 100.Chilton L, Giles WR, Smith GL. Evidence of intercellular coupling between co‐cultured adult rabbit ventricular myocytes and myofibroblasts. J Physiol 583: 225‐236, 2007.
 101.Chinnadurai R, Copland IB, Patel SR, Galipeau J. IDO‐independent suppression of T cell effector function by IFN‐gamma‐licensed human mesenchymal stromal cells. J Immunol 192: 1491‐1501, 2014.
 102.Chiono V, Mozetic P, Boffito M, Sartori S, Gioffredi E, Silvestri A, Rainer A, Giannitelli SM, Trombetta M, Nurzynska D, Meglio FD, Castaldo C, Miraglia R, Montagnani S, Ciardelli G. Polyurethane‐based scaffolds for myocardial tissue engineering. Interface Focus 4: 1‐11, 2014.
 103.Choy L, Yeo JM, Tse V, Chan SP, Tse G. Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models. Int J Cardiol Heart Vasc 12: 1‐10, 2016.
 104.Christman KL, Fok HH, Sievers RE, Fang Q, Lee RJ. Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction. Tissue Eng 10: 403‐409, 2004.
 105.Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ. Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 44: 2004.
 106.Clarke C, Flores‐Munoz M, McKinney CA, Milligan G, Nicklin SA. Regulation of cardiovascular remodeling by the counter‐regulatory axis of the renin‐angiotensin system. Future Cardiol 9: 23‐38, 2013.
 107.Cleutjens JP, Blankesteijn WM, Daemen MJ, Smits JF. The infarcted myocardium: Simply dead tissue, or a lively target for therapeutic interventions. Cardiovasc Res 44: 232‐241, 1999.
 108.Cleutjens JP, Kandala JC, Guarda E, Guntaka RV, Weber KT. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 27: 1281‐1292, 1995.
 109.Cohen SB, Zheng G, Heyman HC, Stavnezer E. Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents. Nucleic Acids Res 27: 1006‐1014, 1999.
 110.Colosi C, Shin SR, Manoharan V, Massa S, Costantini M, Barbetta A, Dokmeci MR, Dentini M, Khademhosseini A. Microfluidic bioprinting of heterogeneous 3D tissue constructs using low‐viscosity bioink. Adv Mater 28: 677‐684, 2016.
 111.Condorelli G, Jotti GS, Pagiatakis C. Fibroblast senescence as a therapeutic target of myocardial fibrosis: Beyond spironolactone? J Am Coll Cardiol 67: 2029‐2031, 2016.
 112.Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A. Human mesenchymal stem cells modulate B‐cell functions. Blood 107: 367‐372, 2006.
 113.Cowan PM, McGavin S, North AC. The polypeptide chain configuration of collagen. Nature 176: 1062‐1064, 1955.
 114.Crabtree GR. Calcium, calcineurin, and the control of transcription. J Biol Chem 276: 2313‐2316, 2001.
 115.Creemers EE, Cleutjens JP, Smits JF, Daemen MJ. Matrix metalloproteinase inhibition after myocardial infarction: A new approach to prevent heart failure? Circ Res 89: 201‐210, 2001.
 116.Creemers EE, Davis JN, Parkhurst AM, Leenders P, Dowdy KB, Hapke E, Hauet AM, Escobar PG, Cleutjens JP, Smits JF, Daemen MJ, Zile MR, Spinale FG. Deficiency of TIMP‐1 exacerbates LV remodeling after myocardial infarction in mice. Am J Physiol Heart Circ Physiol 284: H364‐H371, 2003.
 117.Cunnington RH, Northcott JM, Ghavami S, Filomeno KL, Jahan F, Kavosh MS, Davies JJ, Wigle JT, Dixon IM. The Ski‐Zeb2‐Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype. J Cell Sci 127: 40‐49, 2014.
 118.Cunnington RH, Wang B, Ghavami S, Bathe KL, Rattan SG, Dixon IM. Antifibrotic properties of c‐Ski and its regulation of cardiac myofibroblast phenotype and contractility. Am J Physiol Cell Physiol 300: C176‐C186, 2011.
 119.Cuspidi C, Rescaldani M, Tadic M, Sala C, Grassi G. Effects of bariatric surgery on cardiac structure and function: A systematic review and meta‐analysis. Am J Hypertens 27: 146‐156, 2014.
 120.Cutts J, Nikkhah M, Brafman DA. Biomaterial approaches for stem cell‐based myocardial tissue engineering. Biomark Insights 10: 77‐90, 2015.
 121.D'Amore A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor‐mediated hypertrophy. Hypertension 46: 1347‐1354, 2005.
 122.Darby I, Skalli O, Gabbiani G. Alpha‐smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 63: 21‐29, 1990.
 123.Daskalopoulos EP, Janssen BJ, Blankesteijn WM. Targeting Wnt signaling to improve wound healing after myocardial infarction. Methods Mol Biol 1037: 355‐380, 2013.
 124.Davis GE, Bayless KJ, Davis MJ, Meininger GA. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am J Pathol 156: 1489‐1498, 2000.
 125.Davis JD, Olsen MA, Bommarito K, LaRue SJ, Saeed M, Rich MW, Vader JM. All‐payer analysis of heart failure hospitalization 30‐day readmission: Comorbidities matter. Am J Med 130: 93. e99‐93. e28, 2017.
 126.Dawn B, Abdel‐Latif A, Sanganalmath SK, Flaherty MP, Zuba‐Surma EK. Cardiac repair with adult bone marrow‐derived cells: The clinical evidence. Antioxid Redox Signal 11: 1865‐1882, 2009.
 127.Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP. CD36 mediates the in vitro inhibitory effects of thrombospondin‐1 on endothelial cells. J Cell Biol 138: 707‐717, 1997.
 128.Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF‐beta signaling. Cell Res 19: 47‐57, 2009.
 129.Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor‐beta 1 induces alpha‐smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122: 103‐111, 1993.
 130.Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 146: 56‐66, 1995.
 131.Dezutter‐Dambuyant C, Durand I, Alberti L, Bendriss‐Vermare N, Valladeau‐Guilemond J, Duc A, Magron A, Morel AP, Sisirak V, Rodriguez C, Cox D, Olive D, Caux C. A novel regulation of PD‐1 ligands on mesenchymal stromal cells through MMP‐mediated proteolytic cleavage. Oncoimmunology 5: e1091146, 2016.
 132.Dhingra S, Huang XP, Li RK. Challenges in allogeneic mesenchymal stem cell‐mediated cardiac repair. Trends Cardiovasc Med 20: 263‐268, 2010.
 133.Dhingra S, Li P, Huang XP, Guo J, Wu J, Mihic A, Li SH, Zang WF, Shen D, Weisel RD, Singal PK, Li RK. Preserving prostaglandin E2 level prevents rejection of implanted allogeneic mesenchymal stem cells and restores postinfarction ventricular function. Circulation 128: S69‐S78, 2013.
 134.Dick SA, Epelman S. Chronic heart failure and inflammation: What do we really know? Circ Res 119: 159‐176, 2016.
 135.Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, Harrison DG, Dikalov SI. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 107: 106‐116, 2010.
 136.Ding B, Abe JI, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C. Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: Implication in heart failure. Circulation 111: 2469‐2476, 2005.
 137.Dini FL, Simioniuc A, Carluccio E, Ghio S, Rossi A, Biagioli P, Reboldi G, Galeotti GG, Lu F, Zara C. Echo and BNP serial assessment in ambulatory heart failure care: Data on loop diuretic use and renal function. Data Brief 9: 1074‐1076, 2016.
 138.Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117: 2825‐2833, 2007.
 139.Diwan A, Matkovich SJ, Yuan Q, Zhao W, Yatani A, Brown JH, Molkentin JD, Kranias EG, Dorn GW, 2nd. Endoplasmic reticulum‐mitochondria crosstalk in NIX‐mediated murine cell death. J Clin Invest 119: 203‐212, 2009.
 140.Diwan A, Wansapura J, Syed FM, Matkovich SJ, Lorenz JN, Dorn GW, II. Nix‐mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation 117: 396‐404, 2008.
 141.Dobaczewski M, de Haan JJ, Frangogiannis NG. The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res 5: 837‐847, 2012.
 142.Dodge‐Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437: 574‐578, 2005.
 143.Dorn GW, II. Physiologic growth and pathologic genes in cardiac development and cardiomyopathy. Trends Cardiovasc Med 15: 185‐189, 2005.
 144.Doukas J, Wrasidlo W, Noronha G, Dneprovskaia E, Fine R, Weis S, Hood J, Demaria A, Soll R, Cheresh D. Phosphoinositide 3‐kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc Natl Acad Sci U S A 103: 19866‐19871, 2006.
 145.Downey JM, Miura T, Eddy LJ, Chambers DE, Mellert T, Hearse DJ, Yellon DM. Xanthine oxidase is not a source of free radicals in the ischemic rabbit heart. J Mol Cell Cardiol 19: 1053‐1060, 1987.
 146.Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destree A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC. Mutations in the TGF‐beta repressor SKI cause Shprintzen‐Goldberg syndrome with aortic aneurysm. Nat Genet 44: 1249‐1254, 2012.
 147.du Pre BC, Doevendans PA, van Laake LW. Stem cells for cardiac repair: An introduction. J Geriatr Cardiol 10: 186‐197, 2013.
 148.Dugina V, Fontao L, Chaponnier C, Vasiliev J, Gabbiani G. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors. J Cell Sci 114: 3285‐3296, 2001.
 149.Dunlay SM, Redfield MM, Weston SA, Therneau TM, Long KH, Shah ND, Roger VL. Hospitalizations after heart failure diagnosis: A community perspective. J Am Coll Cardiol 54: 1695‐1702, 2009.
 150.Dvir T, Kedem A, Ruvinov E, Levy O, Freeman I, Landa N, Holbova R. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc Natl Acad Sci U S A 106: 14990‐14995, 2009.
 151.Dvir T, Timko BP, Brigham MD, Naik SR, Karajanagi SS, Levy O, Jin H, Parker KK, Langer R, Kohane DS. Nanowired three‐dimensional cardiac patches. Nat Nanotechnol 6: 720‐725, 2011.
 152.Dvir T, Timko BP, Kohane DS, Langer R. Nanotechnological strategies for engineering complex tissues. Nat Nanotechnol 6: 13‐22, 2011.
 153.Edlund S, Landstrom M, Heldin CH, Aspenstrom P. Transforming growth factor‐beta‐induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13: 902‐914, 2002.
 154.Edwards E, Patel S, DiPette DJ. Resistant hypertension: Is there a pathophysiologic role for the metalloproteinase system? J Clin Hypertens 18: 966‐968, 2016.
 155.El‐Sherbiny IM, Yacoub MH. Hydrogel scaffolds for tissue engineering: Progress and challenges. Glob Cardiol Sci Pract 213: 316‐342, 2013.
 156.Engel ME, McDonnell MA, Law BK, Moses HL. Interdependent SMAD and JNK signaling in transforming growth factor‐beta‐mediated transcription. J Biol Chem 274: 37413‐37420, 1999.
 157.Engelmayr GC, Cheng M, Bettinger CJ, Borenstein JT, Langer R, Freed LE. Accordion‐like honeycombs for tissue engineering of cardiac anisotropy. Nat Mater 7: 1003‐1010, 2008.
 158.Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O'Donnell SE, Aykin‐Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME. A dynamic pathway for calcium‐independent activation of CaMKII by methionine oxidation. Cell 133: 462‐474, 2008.
 159.Espira L, Czubryt MP. Emerging concepts in cardiac matrix biology. Can J Physiol Pharmacol 87: 996‐1008, 2009.
 160.Espira L, Lamoureux L, Jones SC, Gerard RD, Dixon IM, Czubryt MP. The basic helix‐loop‐helix transcription factor scleraxis regulates fibroblast collagen synthesis. J Mol Cell Cardiol 47: 188‐195, 2009.
 161.Evans RA, Tian YC, Steadman R, Phillips AO. TGF‐beta1‐mediated fibroblast‐myofibroblast terminal differentiation‐–the role of Smad proteins. Exp Cell Res 282: 90‐100, 2003.
 162.Fan L, Hu C, Chen J, Cen P, Wang J, Li L. Interaction between mesenchymal stem cells and B‐cells. Int J Mol Sci 17: 2016.
 163.Federation WH. Cardiovascular Disease: Risk Factors ‐ Fact Sheet. 2011.
 164.Fei AH, Wang FC, Wu ZB, Pan SM. Phosphocreatine attenuates angiotensin II‐induced cardiac fibrosis in rat cardiomyocytes through modulation of MAPK and NF‐kappaB pathway. Eur Rev Med Pharmacol Sci 20: 2726‐2733, 2016.
 165.Feng YH, Fu P. Dual blockade of the renin‐angiotensin‐aldosterone system in type 2 diabetic kidney disease. Chin Med J (Engl) 129: 81‐87, 2016.
 166.ffrench‐Constant C. Alternative splicing of fibronectin – many different proteins but few different functions. Exp Cell Res 221: 261‐271, 1995.
 167.Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun G. Anakinra, a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo‐controlled trial. Arthritis Rheum 48: 927‐934, 2003.
 168.Flevaris P, Vaughan D. The role of plasminogen activator inhibitor type‐1 in fibrosis. Semin Thromb Hemost 43: 169‐177, 2016.
 169.Foster JG, Blunt MD, Carter E, Ward SG. Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol Rev 64: 1027‐1054, 2012.
 170.Francis Stuart SD, De Jesus NM, Lindsey ML, Ripplinger CM. The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. J Mol Cell Cardiol 91: 114‐122, 2016.
 171.Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev 92: 635‐688, 2012.
 172.Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res 110: 159‐173, 2012.
 173.Frangogiannis NG. Interleukin‐1 in cardiac injury, repair, and remodeling: Pathophysiologic and translational concepts. Discoveries (Craiova) 3: pii: e41, 2015.
 174.Franssen C, Gonzalez Miqueo A. The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction. Neth Heart J 24: 259‐267, 2016.
 175.Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci 123: 4195‐4200, 2010.
 176.Frantz S, Nahrendorf M. Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res 102: 240‐248, 2014.
 177.Frey N, Linke A, Süselbeck T, Müller‐Ehmsen J, Vermeersch P, Schoors D, Rosenberg M, Bea F, Tuvia S, Leor J. Intracoronary delivery of injectable bioabsorbable scaffold (IK‐5001) to treat left ventricular remodeling after ST‐elevation myocardial infarction. Circ Cardiovasc Interv 7: 806‐812, 2014.
 178.Frey N, Olson EN. Cardiac hypertrophy: The good, the bad, and the ugly. Annu Rev Physiol 65: 45‐79, 2003.
 179.Fujimoto KL, Ma Z, Nelson DM, Hashizume R, Guan J, Tobita K, Wagner WR. Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium. Biomaterials 30: 4357‐4368, 2009.
 180.Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Suzuki S, Kitagawa M, Hishida A. Ubiquitin‐dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney Int 69: 1733‐1740, 2006.
 181.Fukushima M, Nakamuta M, Kohjima M, Kotoh K, Enjoji M, Kobayashi N, Nawata H. Fasudil hydrochloride hydrate, a Rho‐kinase (ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. Liver Int 25: 829‐838, 2005.
 182.Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, Yamagata H, Matsushita M, Seki T, Inagaki Y, Nishizawa M, Fujisawa J, Inoue K. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology 38: 879‐889, 2003.
 183.Furumatsu T, Shukunami C, Amemiya‐Kudo M, Shimano H, Ozaki T. Scleraxis and E47 cooperatively regulate the Sox9‐dependent transcription. Int J Biochem Cell Biol 42: 148‐156, 2010.
 184.Gallina C, Turinetto V, Giachino C. A new paradigm in cardiac regeneration: The mesenchymal stem cell secretome. Stem Cells Int 2015: 765846, 2015.
 185.Gang H, Dhingra R, Wang Y, Mughal W, Gordon JW, Kirshenbaum LA. Epigenetic regulation of E2F‐1‐dependent Bnip3 transcription and cell death by nuclear factor‐kappaB and histone deacetylase‐1. Pediatr Cardiol 32: 263‐266, 2011.
 186.Garikipati VN, Jadhav S, Pal L, Prakash P, Dikshit M, Nityanand S. Mesenchymal stem cells from fetal heart attenuate myocardial injury after infarction: An in vivo serial pinhole gated SPECT‐CT study in rats. PLoS One 9: e100982, 2014.
 187.Geneste O, Copeland JW, Treisman R. LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics. J Cell Biol 157: 831‐838, 2002.
 188.Georgiadis V, Knight RA, Jayasinghe SN, Stephanou A. Cardiac tissue engineering: Renewing the arsenal for the battle against heart disease. Integr Biol 6: 111‐126, 2014.
 189.Ghonim S, Voges I, Gatehouse PD, Keegan J, Gatzoulis MA, Kilner PJ, Babu‐Narayan SV. Myocardial architecture, mechanics, and fibrosis in congenital heart disease. Front Cardiovasc Med 4: 30, 2017.
 190.Giannakos E, Vardali E, Bartekova M, Fogarassyova M, Barancik M, Radosinska J. Changes in activities of circulating MMP‐2 and MMP‐9 in patients suffering from heart failure in relation to gender, hypertension and treatment: A cross‐sectional study. Physiol Res 65(Suppl 1): S149‐S152, 2016.
 191.Givertz MM. Manipulation of the renin‐angiotensin system. Circulation 104: e14‐e18, 2001.
 192.Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105: 2821‐2827, 2005.
 193.Godin CM, Ferguson SS. Biased agonism of the angiotensin II type 1 receptor. Mini Rev Med Chem 12: 812‐816, 2012.
 194.Goldenberg I, Jonas M, Tenenbaum A, Boyko V, Matetzky S, Shotan A, Behar S, Reicher‐Reiss H. Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med 163: 2301‐2305, 2003.
 195.Gordon JW. Regulation of cardiac myocyte cell death and differentiation by myocardin. Mol Cell Biochem 2017.
 196.Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF‐kappaB in the heart: To be or not to NF‐kappaB. Circ Res 108: 1122‐1132, 2011.
 197.Govindarajan G, Eble DM, Lucchesi PA, Samarel AM. Focal adhesion kinase is involved in angiotensin II‐mediated protein synthesis in cultured vascular smooth muscle cells. Circ Res 87: 710‐716, 2000.
 198.Greer SN, Metcalf JL, Wang Y, Ohh M. The updated biology of hypoxia‐inducible factor. EMBO J 31: 2448‐2460, 2012.
 199.Grimes HL, Ambrose MR, Goodenow MM. C‐ski transcripts with and without exon 2 are expressed in skeletal muscle and throughout chick embryogenesis. Oncogene 8: 2863‐2868, 1993.
 200.Grimes HL, Szente BE, Goodenow MM. C‐ski cDNAs are encoded by eight exons, six of which are closely linked within the chicken genome. Nucleic Acids Res 20: 1511‐1516, 1992.
 201.Grosberg A, Nesmith AP, Goss JA, Brigham MD, McCain ML, Parker KK. Muscle on a chip: In vitro contractility assays for smooth and striated muscle. J Pharmacol Toxicol Methods 65: 126‐135, 2012.
 202.Gu H, Mickler EA, Cummings OW, Sandusky GE, Weber DJ, Gracon A, Woodruff T, Wilkes DS, Vittal R. Crosstalk between TGF‐beta1 and complement activation augments epithelial injury in pulmonary fibrosis. FASEB J 28: 4223‐4234, 2014.
 203.Gullestad L, Aass H, Fjeld JG, Wikeby L, Andreassen AK, Ihlen H, Simonsen S, Kjekshus J, Nitter‐Hauge S, Ueland T, Lien E, Froland SS, Aukrust P. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 103: 220‐225, 2001.
 204.Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater 5: 1‐16; discussion 16, 2003.
 205.Hafizi S, Wharton J, Chester AH, Yacoub MH. Profibrotic effects of endothelin‐1 via the ETA receptor in cultured human cardiac fibroblasts. Cell Physiol Biochem 14: 285‐292, 2004.
 206.Halade GV, Kain V, Black LM, Prabhu SD, Ingle KA. Aging dysregulates D‐ and E‐series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. Aging (Albany NY) 8: 2611‐2634, 2016.
 207.Halade GV, Kain V, Ingle KA. Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology. Am J Physiol Heart Circ Physiol 314: H255‐H267, 2018.
 208.Ham SA, Kim HJ, Kim HJ, Kang ES, Eun SY, Kim GH, Park MH, Woo IS, Kim HJ, Chang KC, Lee JH, Seo HG. PPARdelta promotes wound healing by up‐regulating TGF‐beta1‐dependent or ‐independent expression of extracellular matrix proteins. J Cell Mol Med 14: 1747‐1759, 2010.
 209.Han H, Hu J, Yan Q, Zhu J, Zhu Z, Chen Y, Sun J, Zhang R. Bone marrow‐derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep 13: 1517‐1524, 2016.
 210.Hanafusa H, Ninomiya‐Tsuji J, Masuyama N, Nishita M, Fujisawa J, Shibuya H, Matsumoto K, Nishida E. Involvement of the p38 mitogen‐activated protein kinase pathway in transforming growth factor‐beta‐induced gene expression. J Biol Chem 274: 27161‐27167, 1999.
 211.Hao J, Wang B, Jones SC, Jassal DS, Dixon IM. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol Heart Circ Physiol 279: H3020‐H3030, 2000.
 212.Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB, Jr., Reisman MA, Schaer GL, Sherman W. A randomized, double‐blind, placebo‐controlled, dose‐escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54: 2277‐2286, 2009.
 213.Harrison BC, Kim MS, van Rooij E, Plato CF, Papst PJ, Vega RB, McAnally JA, Richardson JA, Bassel‐Duby R, Olson EN, McKinsey TA. Regulation of cardiac stress signaling by protein kinase d1. Mol Cell Biol 26: 3875‐3888, 2006.
 214.Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 107: 913‐922, 2010.
 215.Hatzistergos KE, Saur D, Seidler B, Balkan W, Breton M, Valasaki K, Takeuchi LM, Landin AM, Khan A, Hare JM. Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways. Circ Res 119: 921‐930, 2016.
 216.He J, Tegen SB, Krawitz AR, Martin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem 278: 30540‐30547, 2003.
 217.Heart Outcomes Prevention Evaluation Study I, Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin‐converting‐enzyme inhibitor, ramipril, on cardiovascular events in high‐risk patients. N Engl J Med 342: 145‐153, 2000.
 218.Heldin CH, Miyazono K, ten Dijke P. TGF‐beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465‐471, 1997.
 219.Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, Mushtaq M, Williams AR, Suncion VY, McNiece IK, Ghersin E, Soto V, Lopera G, Miki R, Willens H, Hendel R, Mitrani R, Pattany P, Feigenbaum G, Oskouei B, Byrnes J, Lowery MH, Sierra J, Pujol MV, Delgado C, Gonzalez PJ, Rodriguez JE, Bagno LL, Rouy D, Altman P, Foo CW, da Silva J, Anderson E, Schwarz R, Mendizabal A, Hare JM. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC‐HFT randomized trial. JAMA 311: 62‐73, 2014.
 220.Heyman HC, Stavnezer E. A carboxyl‐terminal region of the ski oncoprotein mediates homodimerization as well as heterodimerization with the related protein SnoN. J Biol Chem 269: 26996‐27003, 1994.
 221.Heymans S, Schroen B, Vermeersch P, Milting H, Gao F, Kassner A, Gillijns H, Herijgers P, Flameng W, Carmeliet P, Van de Werf F, Pinto YM, Janssens S. Increased cardiac expression of tissue inhibitor of metalloproteinase‐1 and tissue inhibitor of metalloproteinase‐2 is related to cardiac fibrosis and dysfunction in the chronic pressure‐overloaded human heart. Circulation 112: 1136‐1144, 2005.
 222.Higaki M, Shimokado K. Phosphatidylinositol 3‐kinase is required for growth factor‐induced amino acid uptake by vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19: 2127‐2132, 1999.
 223.Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signal transduction through the AT1 receptor: Novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112: 417‐428, 2007.
 224.Hilfiker‐Kleiner D, Landmesser U, Drexler H. Molecular mechanisms in heart failure: Focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll Cardiol 48: A56‐A66, 2006.
 225.Hingtgen SD, Tian X, Yang J, Dunlay SM, Peek AS, Wu Y, Sharma RV, Engelhardt JF, Davisson RL. Nox2‐containing NADPH oxidase and Akt activation play a key role in angiotensin II‐induced cardiomyocyte hypertrophy. Physiol Genomics 26: 180‐191, 2006.
 226.Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 159: 1009‐1020, 2001.
 227.Hsu YH, Sarker KP, Pot I, Chan A, Netherton SJ, Bonni S. Sumoylated SnoN represses transcription in a promoter‐specific manner. J Biol Chem 281: 33008‐33018, 2006.
 228.Hu J, Sun X, Ma H, Xie C, Chen YE, Ma PX. Porous nanofibrous PLLA scaffolds for vascular tissue engineering. Biomaterials 31: 7971‐7977, 2010.
 229.Ifkovits JL, Tous E, Minakawa M, Morita M, Robb JD, Koomalsingh KJ, Gorman JH, Gorman RC, Burdick JA. Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model. Proc Natl Acad Sci U S A 107: 11507‐11512, 2010.
 230.Ikeda Y, Kumagai H, Motozawa Y, Suzuki J, Komuro I. Biased agonism of the angiotensin II type I receptor. Int Heart J 56: 485‐488, 2015.
 231.Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR, Prabhu SD. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res 114: 266‐282, 2014.
 232.Iyer RP, Jung M, Lindsey ML. MMP‐9 signaling in the left ventricle following myocardial infarction. Am J Physiol Heart Circ Physiol 311: H190‐H198, 2016.
 233.Izzo V, Bravo‐San Pedro JM, Sica V, Kroemer G, Galluzzi L. Mitochondrial permeability transition: New findings and persisting uncertainties. Trends Cell Biol 26: 655‐667, 2016.
 234.Javelaud D, Mauviel A. Crosstalk mechanisms between the mitogen‐activated protein kinase pathways and Smad signaling downstream of TGF‐beta: Implications for carcinogenesis. Oncogene 24: 5742‐5750, 2005.
 235.Jawad H, Ali NN, Lyon AR, Chen QZ, Harding SE, Boccaccini AR. Myocardial tissue engineering: A review. J Tissue Eng Regen Med 1: 327‐342, 2007.
 236.Jeevanantham V, Afzal MR, Zuba‐Surma EK, Dawn B. Clinical trials of cardiac repair with adult bone marrow‐derived cells. Methods Mol Biol 1036: 179‐205, 2013.
 237.Jensen BC, Bultman SJ, Holley D, Tang W, de Ridder G, Pizzo S, Bowles D, Willis MS. Upregulation of autophagy genes and the unfolded protein response in human heart failure. Int J Clin Exp Med 10: 1051‐1058, 2017.
 238.Jin J, Jeong SI, Shin YM, Lim KS, Shin H, Lee YM, Koh HC, Kim KS. Transplantation of mesenchymal stem cells within a poly(lactide‐co‐epsilon‐caprolactone) scaffold improves cardiac function in a rat myocardial infarction model. Eur J Heart Fail 11: 147‐153, 2009.
 239.Jones S. An overview of the basic helix‐loop‐helix proteins. Genome Biol 5: 226, 2004.
 240.Jongpaiboonkit L, King WJ, Lyons GE, Paguirigan AL, Warrick JW, Beebe DJ, Murphy WL. An adaptable hydrogel array format for 3‐dimensional cell culture and analysis. Biomaterials 29: 3346‐3356, 2008.
 241.Ju H, Dixon IM. Extracellular matrix and cardiovascular diseases. Can J Cardiol 12: 1259‐1267, 1996.
 242.Ju H, Hao J, Zhao S, Dixon IM. Antiproliferative and antifibrotic effects of mimosine on adult cardiac fibroblasts. Biochim Biophys Acta 1448: 51‐60, 1998.
 243.Justus DE, Hoffman A, Mironova E, Hartman A, Goldsmith JG, Potts JD, Goldsmith EC. Discoidin domain receptors in cardiac development. In: Discoidin Domain Receptors in Health and Disease. Springer New York: Springer, 2016, pp. 331‐347.
 244.Kagan HM, Trackman PC. Properties and function of lysyl oxidase. Am J Respir Cell Mol Biol 5: 206‐210, 1991.
 245.Kain V, Ingle KA, Colas RA, Dalli J, Prabhu SD, Serhan CN, Joshi M, Halade GV. Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. J Mol Cell Cardiol 84: 24‐35, 2015.
 246.Kain V, Prabhu SD, Halade GV. Inflammation revisited: Inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol 109: 444, 2014.
 247.Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2: 702‐714, 2014.
 248.Karch J, Molkentin JD. Regulated necrotic cell death: The passive aggressive side of Bax and Bak. Circ Res 116: 1800‐1809, 2015.
 249.Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D. PD‐L1 co‐stimulation contributes to ligand‐induced T cell receptor down‐modulation on CD8+ T cells. EMBO Mol Med 3: 581‐592, 2011.
 250.Kassiri Z, Oudit GY, Sanchez O, Dawood F, Mohammed FF, Nuttall RK, Edwards DR, Liu PP, Backx PH, Khokha R. Combination of tumor necrosis factor‐alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase‐3 knock‐out mice. Circ Res 97: 380‐390, 2005.
 251.Kawano H, Cody RJ, Graf K, Goetze S, Kawano Y, Schnee J, Law RE, Hsueh WA. Angiotensin II enhances integrin and alpha‐actinin expression in adult rat cardiac fibroblasts. Hypertension 35: 273‐279, 2000.
 252.Kawano H, Do YS, Kawano Y, Starnes V, Barr M, Law RE, Hsueh WA. Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation 101: 1130‐1137, 2000.
 253.Kehat I, Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 122: 2727‐2735, 2010.
 254.Keyes KT, Ye Y, Lin Y, Zhang C, Perez‐Polo JR, Gjorstrup P, Birnbaum Y. Resolvin E1 protects the rat heart against reperfusion injury. Am J Physiol Heart Circ Physiol 299: H153‐H164, 2010.
 255.Khaddash I, Hawatmeh A, Altheeb Z, Hamdan A, Shamoon F. An unusual cause of postpartum heart failure. Ann Card Anaesth 20: 102, 2017.
 256.Khademhosseini A, Langer R, Borenstein J, Vacanti JP. Microscale technologies for tissue engineering and biology. Proc Natl Acad Sci U S A 103: 2480‐2487, 2006.
 257.Kharaziha M, Memic A, Akbari M, Brafman DA, Nikkhah M. Nano‐enabled approaches for stem cell‐based cardiac tissue engineering. Adv Healthc Mater 2016.
 258.Kharaziha M, Nikkhah M, Shin S‐R, Annabi N, Masoumi N, Gaharwar AK, Camci‐Unal G, Khademhosseini A. PGS: Gelatin nanofibrous scaffolds with tunable mechanical and structural properties for engineering cardiac tissues. Biomaterials 34: 6355‐6366, 2013.
 259.Kim EH, Galchev VI, Kim JY, Misek SA, Stevenson TK, Campbell MD, Pagani FD, Day SM, Johnson TC, Washburn JG, Vikstrom KL, Michele DE, Misek DE, Westfall MV. Differential protein expression and basal lamina remodeling in human heart failure. Proteomics Clin Appl 10: 585‐596, 2016.
 260.Kim S, Lee Y, Seo JE, Cho KH, Chung JH. Caveolin‐1 increases basal and TGF‐beta1‐induced expression of type I procollagen through PI‐3 kinase/Akt/mTOR pathway in human dermal fibroblasts. Cell Signal 20: 1313‐1319, 2008.
 261.Kiyono K, Suzuki HI, Morishita Y, Komuro A, Iwata C, Yashiro M, Hirakawa K, Kano MR, Miyazono K. c‐Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor‐beta signaling in diffuse‐type gastric carcinoma. Cancer Sci 100: 1809‐1816, 2009.
 262.Kobayashi N, Goto K, Horiguchi K, Nagata M, Kawata M, Miyazawa K, Saitoh M, Miyazono K. c‐Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases. Genes Cells 12: 375‐385, 2007.
 263.Kofidis T, Müller‐Stahl K, Haverich A. Myocardial restoration and tissue engineering of heart structures. In: Hauser H, Fussenegger M, editors. Tissue Engineering. Springer Nature Switzerland AG: Humana Press, 2007, pp. 273‐290.
 264.Kohl P, Camelliti P, Burton FL, Smith GL. Electrical coupling of fibroblasts and myocytes: Relevance for cardiac propagation. J Electrocardiol 38: 45‐50, 2005.
 265.Koike N, Fukumura D, Gralla O, Au P, Schechner JS, Jain RK. Tissue engineering: Creation of long‐lasting blood vessels. Nature 428: 138‐139, 2004.
 266.Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell‐free regeneration. Cytotherapy 18: 13‐24, 2016.
 267.Kosaki K, Takahashi D, Udaka T, Kosaki R, Matsumoto M, Ibe S, Isobe T, Tanaka Y, Takahashi T. Molecular pathology of Shprintzen‐Goldberg syndrome. Am J Med Genet A 140: 104‐108; author reply 109‐110, 2006.
 268.Kraehenbuehl TP, Langer R, Ferreira LS. Three‐dimensional biomaterials for the study of human pluripotent stem cells. Nat Methods 8: 731‐736, 2011.
 269.Kraehenbuehl TP, Zammaretti P, Vlies AJVd, Schoenmakers RG, Lutolf MP, Jaconi ME, Hubbell JA. Three‐dimensional extracellular matrix‐directed cardioprogenitor differentiation: Systematic modulation of a synthetic cell‐responsive PEG‐hydrogel. Biomaterials 29: 2757‐2766, 2008.
 270.Krenning G, Zeisberg EM, Kalluri R. The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol 225: 631‐637, 2010.
 271.Krymskaya VP, Hoffman R, Eszterhas A, Ciocca V, Panettieri RA, Jr. TGF‐beta 1 modulates EGF‐stimulated phosphatidylinositol 3‐kinase activity in human airway smooth muscle cells. Am J Physiol 273: L1220‐L1227, 1997.
 272.Kuroda J, Sadoshima J. NADPH oxidase and cardiac failure. J Cardiovasc Transl Res 3: 314‐320, 2010.
 273.Kutschka I, Chen IY, Kofidis T, Arai T, Degenfeld Gv, Sheikh AY, Hendry SL, Pearl J, Hoyt G, Sista R, Yang PC, Blau HM, Gambhir SS, Robbins RC. Collagen matrices enhance survival of transplanted cardiomyoblasts and contribute to functional improvement of ischemic rat hearts. Circulation 114: I167‐I173., 2006.
 274.Kwong JQ, Molkentin JD. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab 21: 206‐214, 2015.
 275.Kyurkchiev D, Bochev I, Ivanova‐Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, Kyurkchiev S. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells 6: 552‐570, 2014.
 276.Lagrand WK, Niessen HW, Wolbink GJ, Jaspars LH, Visser CA, Verheugt FW, Meijer CJ, Hack CE. C‐reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 95: 97‐103, 1997.
 277.Lal H, Verma SK, Golden HB, Foster DM, Smith M, Dostal DE. Stretch‐induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: Opposing roles of JNK1/2 and p38alpha MAP kinases. J Mol Cell Cardiol 45: 770‐778, 2008.
 278.Lamba MS, Abraham MWT. Alterations in adrenergic receptor signaling in heart failure. Heart Fail Rev 5: 7‐16, 2000.
 279.Landa N, Miller L, Feinberg MS, Holbova R, Shachar M, Freeman I, Cohen S, Leor J. Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation 117: 1388‐1396, 2008.
 280.Lanza R, Langer R, Vacanti JP. Principles of Tissue Engineering. Elsevier, Burlington, USA: Academic press, 2011.
 281.Leal J, Luengo‐Fernandez R, Gray A, Petersen S, Rayner M. Economic burden of cardiovascular diseases in the enlarged European Union. Eur Heart J 27: 1610‐1619, 2006.
 282.Lecour S, Smith RM, Woodward B, Opie LH, Rochette L, Sack MN. Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol 34: 509‐518, 2002.
 283.Ledent V, Paquet O, Vervoort M. Phylogenetic analysis of the human basic helix‐loop‐helix proteins. Genome Biol 3: 1‐18 RESEARCH0030, 2002.
 284.Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R. TGF‐beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26: 3957‐3967, 2007.
 285.Leferovich JM, Lana DP, Sutrave P, Hughes SH, Kelly AM. Regulation of c‐ski transgene expression in developing and mature mice. J Neurosci 15: 596‐603, 1995.
 286.Lei PP, Qu YQ, Shuai Q, Tao SM, Bao YX, Wang Y, Wang SW, Wang DH. Fibrocytes are associated with the fibrosis of coronary heart disease. Pathol Res Pract 209: 36‐43, 2013.
 287.Lejard V, Brideau G, Blais F, Salingcarnboriboon R, Wagner G, Roehrl MH, Noda M, Duprez D, Houillier P, Rossert J. Scleraxis and NFATc regulate the expression of the pro‐alpha1(I) collagen gene in tendon fibroblasts. J Biol Chem 282: 17665‐17675, 2007.
 288.Leor J, Amsalem Y, Cohen S. Cells, scaffolds, and molecules for myocardial tissue engineering. Pharmacol Ther 105: 151‐163, 2005.
 289.Levay AK, Peacock JD, Lu Y, Koch M, Hinton RB, Jr., Kadler KE, Lincoln J. Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo. Circ Res 103: 948‐956, 2008.
 290.Li AH, Liu PP, Villarreal FJ, Garcia RA. Dynamic changes in myocardial matrix and relevance to disease: Translational perspectives. Circ Res 114: 916‐927, 2014.
 291.Li CY, Wu XY, Tong JB, Yang XX, Zhao JL, Zheng QF, Zhao GB, Ma ZJ. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno‐free conditions for cell therapy. Stem Cell Res Ther 6: 55, 2015.
 292.Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin‐converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing‐induced congestive heart failure. Circulation 104: 2608‐2614, 2001.
 293.Li J, Li P, Zhang Y, Li GB, He FT, Zhou YG, Yang K, Dai SS. Upregulation of ski in fibroblast is implicated in the peroxisome proliferator–activated receptor delta‐mediated wound healing. Cell Physiol Biochem 30: 1059‐1071, 2012.
 294.Li P, Li SH, Wu J, Zang WF, Dhingra S, Sun L, Weisel RD, Li RK. Interleukin‐6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege. J Cell Mol Med 17: 1136‐1145, 2013.
 295.Li P, Liu P, Xiong RP, Chen XY, Zhao Y, Lu WP, Liu X, Ning YL, Yang N, Zhou YG. Ski, a modulator of wound healing and scar formation in the rat skin and rabbit ear. J Pathol 223: 659‐671, 2011.
 296.Li R‐K, Jia Z‐QH, Weisel RD, Mickle DAG, Choi A, Yau TM. Survival and function of bioengineered cardiac grafts. Circulation 100: II‐63‐Ii‐69, 1999.
 297.Li Y, Turck CM, Teumer JK, Stavnezer E. Unique sequence, ski, in Sloan‐Kettering avian retroviruses with properties of a new cell‐derived oncogene. J Virol 57: 1065‐1072, 1986.
 298.Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 104: 1147‐1152, 2001.
 299.Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L. The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 277: 14467‐14474, 2002.
 300.Liehn EA, Postea O, Curaj A, Marx N. Repair after myocardial infarction, between fantasy and reality: The role of chemokines. J Am Coll Cardiol 58: 2357‐2362, 2011.
 301.Lijnen P, Petrov V, Rumilla K, Fagard R. Stimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts. J Renin Angiotensin Aldosterone Syst 3: 160‐166, 2002.
 302.Lijnen PJ, Petrov VV. Role of intracardiac renin‐angiotensin‐aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol 25: 541‐564, 2003.
 303.Lijnen PJ, Petrov VV, Fagard RH. Angiotensin II‐induced stimulation of collagen secretion and production in cardiac fibroblasts is mediated via angiotensin II subtype 1 receptors. J Renin Angiotensin Aldosterone Syst 2: 117‐122, 2001.
 304.Liu L, Eisen HJ. Epidemiology of heart failure and scope of the problem. Cardiol Clin 32: 1‐8, 2014.
 305.Liu X, Li P, Liu P, Xiong R, Zhang E, Chen X, Gu D, Zhao Y, Wang Z, Zhou Y. The essential role for c‐Ski in mediating TGF‐beta1‐induced bi‐directional effects on skin fibroblast proliferation through a feedback loop. Biochem J 409: 289‐297, 2008.
 306.Liu X, Sun SQ, Hassid A, Ostrom RS. cAMP inhibits transforming growth factor‐beta‐stimulated collagen synthesis via inhibition of extracellular signal‐regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. Mol Pharmacol 70: 1992‐2003, 2006.
 307.Lloyd‐Jones DM, Nam BH, D'Agostino RB, Sr., Levy D, Murabito JM, Wang TJ, Wilson PW, O'Donnell CJ. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle‐aged adults: A prospective study of parents and offspring. JAMA 291: 2204‐2211, 2004.
 308.Lockhart M, Wirrig E, Phelps A, Wessels A. Extracellular matrix and heart development. Birth Defects Res A Clin Mol Teratol 91: 535‐550, 2011.
 309.Lü S, Wang H, Lu W, Liu S, Lin Q, Li D, Duan C, Hao T, Zhou J, Wang Y, Gao S, Wang. C. Both the transplantation of somatic cell nuclear transfer‐and fertilization‐derived mouse embryonic stem cells with temperature‐responsive chitosan hydrogel improve myocardial performance in infarcted rat hearts. Tissue Eng Part A 16: 1303‐1315, 2010.
 310.Lu W‐N, Lü S‐H, Wang H‐B, Li D‐X, Duan C‐M, Liu Z‐Q, Hao T, He W‐J, Xu B, Fu Q, Song YC, Xie X‐H, Wang C‐Y. Functional improvement of infarcted heart by co‐injection of embryonic stem cells with temperature‐responsive chitosan hydrogel. Tissue Eng Part A 15: 1437‐1447, 2009.
 311.Luna JI, Ciriza J, Garcia‐Ojeda ME, Kong M, Herren A, Lieu DK, Li RA, Fowlkes CC, Khine M, McCloskey KE. Multiscale biomimetic topography for the alignment of neonatal and embryonic stem cell‐derived heart cells. Tissue Eng Part C Methods 17: 579‐588, 2011.
 312.Luo K. Ski and SnoN: Negative regulators of TGF‐beta signaling. Curr Opin Genet Dev 14: 65‐70, 2004.
 313.Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 13: 2196‐2206, 1999.
 314.Lyons GE, Micales BK, Herr MJ, Horrigan SK, Namciu S, Shardy D, Stavnezer E. Protooncogene c‐ski is expressed in both proliferating and postmitotic neuronal populations. Dev Dyn 201: 354‐365, 1994.
 315.Ma Y, Halade GV, Lindsey ML. Extracellular matrix and fibroblast communication following myocardial infarction. J Cardiovasc Transl Res 5: 848‐857, 2012.
 316.Macia‐Heras M, Del Castillo‐Rodriguez N, Navarro González J. The renin–angiotensin–aldosterone system in renal and cardiovascular disease and the effects of its pharmacological blockade. J Diabetes Metab 3: 2, 2012.
 317.Madamanchi A. Beta‐adrenergic receptor signaling in cardiac function and heart failure. Mcgill J Med 10: 99, 2007.
 318.Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res 100: 460‐473, 2007.
 319.Maier LS, Bers DM, Brown JH. Calmodulin and Ca2+/calmodulin kinases in the heart ‐ physiology and pathophysiology. Cardiovasc Res 73: 629‐630, 2007.
 320.Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marban L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, Lardo AC, Gerstenblith G, Marban E. Intracoronary cardiosphere‐derived cells for heart regeneration after myocardial infarction (CADUCEUS): A prospective, randomised phase 1 trial. Lancet 379: 895‐904, 2012.
 321.Mann DL. Inflammatory mediators and the failing heart: Past, present, and the foreseeable future. Circ Res 91: 988‐998, 2002.
 322.Mann DL. The emerging role of innate immunity in the heart and vascular system: For whom the cell tolls. Circ Res 108: 1133‐1145, 2011.
 323.Mann DL. Innate immunity and the failing heart: The cytokine hypothesis revisited. Circ Res 116: 1254‐1268, 2015.
 324.Mann DL, Bristow MR. Mechanisms and models in heart failure the biomechanical model and beyond. Circulation 111: 2837‐2849, 2005.
 325.Mann ZF, Chang W, Lee KY, King KA, Kelley MW. Expression and function of scleraxis in the developing auditory system. PLoS One 8: e75521, 2013.
 326.Manso AM, Kang SM, Ross RS. Integrins, focal adhesions, and cardiac fibroblasts. J Investig Med 57: 856‐860, 2009.
 327.Maquart FX, Simeon A, Pasco S, Monboisse JC. [Regulation of cell activity by the extracellular matrix: the concept of matrikines]. J Soc Biol 193: 423‐428, 1999.
 328.Marc Y, Llorens‐Cortes C. The role of the brain renin‐angiotensin system in hypertension: Implications for new treatment. Prog Neurobiol 95: 89‐103, 2011.
 329.Marcus LS, Hart D, Packer M, Yushak M, Medina N, Danziger RS, Heitjan DF, Katz SD. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double‐blind, placebo‐controlled, randomized crossover trial. Circulation 94: 3184‐3189, 1996.
 330.Mariappan N, Elks CM, Fink B, Francis J. TNF‐induced mitochondrial damage: A link between mitochondrial complex I activity and left ventricular dysfunction. Free Radic Biol Med 46: 462‐470, 2009.
 331.Marote A, Teixeira FG, Mendes‐Pinheiro B, Salgado AJ. MSCs‐derived exosomes: Cell‐secreted nanovesicles with regenerative potential. Front Pharmacol 7: 231, 2016.
 332.Marotte H, Cimaz R. Etanercept ‐ TNF receptor and IgG1 Fc fusion protein: Is it different from other TNF blockers? Expert Opin Biol Ther 14: 569‐572, 2014.
 333.Masur SK, Dewal HS, Dinh TT, Erenburg I, Petridou S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci U S A 93: 4219‐4223, 1996.
 334.Mathers CD, Boerma T, Ma Fat D. Global and regional causes of death. Br Med Bull 92: 7‐32, 2009.
 335.Matsumori A, Furukawa Y, Hashimoto T, Yoshida A, Ono K, Shioi T, Okada M, Iwasaki A, Nishio R, Matsushima K, Sasayama S. Plasma levels of the monocyte chemotactic and activating factor/monocyte chemoattractant protein‐1 are elevated in patients with acute myocardial infarction. J Mol Cell Cardiol 29: 419‐423, 1997.
 336.Mazure NM, Pouyssegur J. Atypical BH3‐domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 5: 868‐869, 2009.
 337.McDevitt TC, Angello JC, Whitney ML, Reinecke H, Hauschka SD, Murry CE, Stayton PS. In vitro generation of differentiated cardiac myofibers on micropatterned laminin surfaces. J Biomed Mater Res 60: 472‐479, 2002.
 338.McDevitt TC, Hauschka KAWSD, Murry CE, Stayton PS. Spatially organized layers of cardiomyocytes on biodegradable polyurethane films for myocardial repair. J Biomed Mater Res A 66: 586‐595, 2003.
 339.McElmurray JH, III, Mukherjee R, New RB, Sampson AC, King MK, Hendrick JW, Goldberg A, Peterson TJ, Hallak H, Zile MR, Spinale FG. Angiotensin‐converting enzyme and matrix metalloproteinase inhibition with developing heart failure: Comparative effects on left ventricular function and geometry. J Pharmacol Exp Ther 291: 799‐811, 1999.
 340.McKinsey TA. Derepression of pathological cardiac genes by members of the CaM kinase superfamily. Cardiovasc Res 73: 667‐677, 2007.
 341.McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371: 993‐1004, 2014.
 342.McMurray JJ, Pitt B, Latini R, Maggioni AP, Solomon SD, Keefe DL, Ford J, Verma A, Lewsey J, Investigators AOoHFT. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 1: 17‐24, 2008.
 343.Meerson FZ. Compensatory hyperfunction of the heart and cardiac insufficiency. Circ Res 10: 250‐258, 1962.
 344.Meerson FZ. A mechanism of hypertrophy and wear of the myocardium. Am J Cardiol 15: 755‐760, 1965.
 345.Meerson FZ, Pshennikova MG. Effect of myocardial hypertrophy on cardiac contractility. Fed Proc Transl Suppl 24: 957‐959, 1965.
 346.Mendis S. Global Status Report on Noncommunicable Diseases 2014. Geneva, Switzerland: World Health Organization, 2014.
 347.Mendis PP, Norrving B editor. Global Atlas on Cardiovascular Disease Prevention and Control. Geneva, Switzerland: World Health Organization, 2011.
 348.Meng XM, Huang XR, Chung AC, Qin W, Shao X, Igarashi P, Ju W, Bottinger EP, Lan HY. Smad2 protects against TGF‐beta/Smad3‐mediated renal fibrosis. J Am Soc Nephrol 21: 1477‐1487, 2010.
 349.Miao R, Lu Y, Xing X, Li Y, Huang Z, Zhong H, Huang Y, Chen AF, Tang X, Li H, Cai J, Yuan H. Regulator of G‐protein signaling 10 negatively regulates cardiac remodeling by blocking mitogen‐activated protein kinase‐extracellular signal‐regulated protein kinase 1/2 signaling. Hypertension 67: 86‐98, 2016.
 350.Mitchell S, Thomas G, Harvey K, Cottell D, Reville K, Berlasconi G, Petasis NA, Erwig L, Rees AJ, Savill J, Brady HR, Godson C. Lipoxins, aspirin‐triggered epi‐lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J Am Soc Nephrol 13: 2497‐2507, 2002.
 351.Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20: 1126‐1167, 2014.
 352.Mizuide M, Hara T, Furuya T, Takeda M, Kusanagi K, Inada Y, Mori M, Imamura T, Miyazawa K, Miyazono K. Two short segments of Smad3 are important for specific interaction of Smad3 with c‐Ski and SnoN. J Biol Chem 278: 531‐536, 2003.
 353.Mizzaci C, Vilela AT, Riera R. Ivabradine as adjuvant treatment for chronic heart failure. The Cochrane Library 2013.
 354.Mollmann H, Nef HM, Kostin S, von Kalle C, Pilz I, Weber M, Schaper J, Hamm CW, Elsasser A. Bone marrow‐derived cells contribute to infarct remodelling. Cardiovasc Res 71: 661‐671, 2006.
 355.Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep 16: 431, 2014.
 356.Moore‐Morris T, Guimaraes‐Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez‐Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM. Resident fibroblast lineages mediate pressure overload‐induced cardiac fibrosis. J Clin Invest 124: 2921‐2934, 2014.
 357.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S. Heart Disease and Stroke Statistics‐2016 Update: A report from the American Heart Association. Circulation 133: e38‐e360, 2016.
 358.Mughal W, Nguyen L, Pustylnik S, da Silva Rosa SC, Piotrowski S, Chapman D, Du M, Alli NS, Grigull J, Halayko AJ, Aliani M, Topham MK, Epand RM, Hatch GM, Pereira TJ, Kereliuk S, McDermott JC, Rampitsch C, Dolinsky VW, Gordon JW. A conserved MADS‐box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells. Cell Death Dis 6: e1944, 2015.
 359.Muir T, Sadler‐Riggleman I, Skinner MK. Role of the basic helix‐loop‐helix transcription factor, scleraxis, in the regulation of Sertoli cell function and differentiation. Mol Endocrinol 19: 2164‐2174, 2005.
 360.Mukherjee D, Sen S. Alteration of collagen phenotypes in ischemic cardiomyopathy. J Clin Invest 88: 1141‐1146, 1991.
 361.Mulder KM. Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 11: 23‐35, 2000.
 362.Munce SEP, Perrier L, Shin S, Adhihetty C, Pitzul K, Nelson MLA, Bayley MT. Strategies to improve the quality of life of persons post‐stroke: Protocol of a systematic review. Syst Rev 6: 184, 2017.
 363.Murchison ND, Price BA, Conner DA, Keene DR, Olson EN, Tabin CJ, Schweitzer R. Regulation of tendon differentiation by scleraxis distinguishes force‐transmitting tendons from muscle‐anchoring tendons. Development 134: 2697‐2708, 2007.
 364.Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56: 777‐783, 1989.
 365.Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN, Hauschka SD, Lassar AB, et al. Interactions between heterologous helix‐loop‐helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58: 537‐544, 1989.
 366.Mushtaq M, DiFede DL, Golpanian S, Khan A, Gomes SA, Mendizabal A, Heldman AW, Hare JM. Rationale and design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (the POSEIDON‐DCM study): A phase I/II, randomized pilot study of the comparative safety and efficacy of transendocardial injection of autologous mesenchymal stem cell vs. allogeneic mesenchymal stem cells in patients with non‐ischemic dilated cardiomyopathy. J Cardiovasc Transl Res 7: 769‐780, 2014.
 367.Mustroph J, Neef S, Maier LS. CaMKII as a target for arrhythmia suppression. Pharmacol Ther 176: 22‐31, 2017.
 368.Muthuraman A, Kaur P. Renin‐angiotensin‐Aldosterone system: A current drug target for the management of neuropathic pain. Curr Drug Targets 17: 178‐195, 2016.
 369.Nag AC. Study of non‐muscle cells of the adult mammalian heart: A fine structural analysis and distribution. Cytobios 28: 41‐61, 1980.
 370.Nagano Y, Koinuma D, Miyazawa K, Miyazono K. Context‐dependent regulation of the expression of c‐Ski protein by Arkadia in human cancer cells. J Biochem 147: 545‐554, 2010.
 371.Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T, Episkopou V, Miyazono K, Miyazawa K. Arkadia induces degradation of SnoN and c‐Ski to enhance transforming growth factor‐beta signaling. J Biol Chem 282: 20492‐20501, 2007.
 372.Nagarajan V, Hernandez AV, Cauthen CA, Starling RC, Tang WW. Usefulness of cell‐mediated immune function in risk stratification for patients with advanced heart failure. Am Heart J 183: 35‐39, 2017.
 373.Nagata M, Goto K, Ehata S, Kobayashi N, Saitoh M, Miyoshi H, Imamura T, Miyazawa K, Miyazono K. Nuclear and cytoplasmic c‐Ski differently modulate cellular functions. Genes Cells 11: 1267‐1280, 2006.
 374.Nagata M, Nagata S, Yuki K, Isogaya K, Saitoh M, Miyazono K, Miyazawa K. Identification of a phosphorylation site in c‐Ski as serine 515. J Biochem 148: 423‐427, 2010.
 375.Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y. Cyclophilin D‐dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652‐658, 2005.
 376.Nelissen‐Vrancken HJ, Debets JJ, Snoeckx LH, Daemen MJ, Smits JF. Time‐related normalization of maximal coronary flow in isolated perfused hearts of rats with myocardial infarction. Circulation 93: 349‐355, 1996.
 377.Neves MF, Cunha AR, Cunha MR, Gismondi RA, Oigman W. The role of renin‐angiotensin‐aldosterone system and its new components in arterial stiffness and vascular aging. High Blood Press Cardiovasc Prev 25: 137‐145, 2018.
 378.Newby AC. Metalloproteinase production from macrophages–‐a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction. Exp Physiol 101: 1327‐1337, 2016.
 379.Nguyen Dinh Cat A, Touyz RM. Cell signaling of angiotensin II on vascular tone: Novel mechanisms. Curr Hypertens Rep 13: 122‐128, 2011.
 380.Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94: 1543‐1553, 2004.
 381.Nicol R, Stavnezer E. Transcriptional repression by v‐Ski and c‐Ski mediated by a specific DNA binding site. J Biol Chem 273: 3588‐3597, 1998.
 382.Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J 20: 2757‐2767, 2001.
 383.Nikkhah M, Eshak N, Zorlutuna P, Annabi N, Castello M, Kim K, Dolatshahi‐Pirouz A, Edalat F, Bae H, Yang Y, Khademhosseini A. Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels. Biomaterials 33: 9009‐9018, 2012.
 384.Nomura N, Sasamoto S, Ishii S, Date T, Matsui M, Ishizaki R. Isolation of human cDNA clones of ski and the ski‐related gene, sno. Nucleic Acids Res 17: 5489‐5500, 1989.
 385.Nomura T, Khan MM, Kaul SC, Dong HD, Wadhwa R, Colmenares C, Kohno I, Ishii S. Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev 13: 412‐423, 1999.
 386.Ohtsuka T, Hamada M, Inoue K, Ohshima K, Sujzuki J, Matsunaka T, Ogimoto A, Hara Y, Shigematsu Y, Higaki J. Relation of circulating interleukin‐6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction. Clin Cardiol 27: 417‐420, 2004.
 387.Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485: 251‐255, 2012.
 388.Ontell M, Kozeka K. The organogenesis of murine striated muscle: A cytoarchitectural study. Am J Anat 171: 133‐148, 1984.
 389.Ontell M, Kozeka K. Organogenesis of the mouse extensor digitorum logus muscle: A quantitative study. Am J Anat 171: 149‐161, 1984.
 390.Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA. Controversies in ventricular remodelling. Lancet 367: 356‐367, 2006.
 391.Oral H, Dorn GW, II, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor‐alpha in the adult mammalian cardiac myocyte. J Biol Chem 272: 4836‐4842, 1997.
 392.Organization WH. Cardiovascular diseases ‐ fact sheet #317. 2013.
 393.Osmancik P, Louckova A. Biomarkers of apoptosis, inflammation and cardiac extracellular matrix remodeling in the prognosis of heart failure. Kardiol Pol 74: 295‐305, 2016.
 394.Oudit GY, Penninger JM. Cardiac regulation by phosphoinositide 3‐kinases and PTEN. Cardiovasc Res 82: 250‐260, 2009.
 395.Packer DL. Congenital long QT syndrome. Rev Cardiovasc Med 2: 26‐28, 2001.
 396.Padda J, Sequiera GL, Sareen N, Dhingra S. Stem cell therapy for cardiac regeneration: Hits and misses. Can J Physiol Pharmacol 93: 835‐841, 2015.
 397.Pagowska‐Klimek I, Cedzynski M. Mannan‐binding lectin in cardiovascular disease. Biomed Res Int 2014: 616817, 2014.
 398.Palomeque J, Delbridge L, Petroff MV. Angiotensin II: A regulator of cardiomyocyte function and survival. Front Biosci (Landmark Ed) 14: 5118‐5133, 2009.
 399.Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci 115: 3861‐3863, 2002.
 400.Papadaki M, Bursac N, Langer R, Merok J, Vunjak‐Novakovic G, Freed LE. Tissue engineering of functional cardiac muscle: Molecular, structural, and electrophysiological studies. Am J Physiol Heart Circ Physiol 280: H168‐H178, 2001.
 401.Park H, Radisic M, Lim J, Chang B, Vunjak‐Novakovic G. A novel composite scaffold for cardiac tissue engineering. In Vitro CellDevBiol‐Animal 41: 188‐196, 2005.
 402.Pat B, Yang T, Kong C, Watters D, Johnson DW, Gobe G. Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants. Kidney Int 67: 931‐943, 2005.
 403.Patel RS, Odermatt E, Schwarzbauer JE, Hynes RO. Organization of the fibronectin gene provides evidence for exon shuffling during evolution. EMBO J 6: 2565‐2572, 1987.
 404.Patra C, Talukdar S, Novoyatleva T, Velagala SR, Mühlfeld C, Kundu B, Kundu SC, Engel FB. Silk protein fibroin from Antheraea mylitta for cardiac tissue engineering. Biomaterials 33: 2673‐2680, 2012.
 405.Pauling L, Corey RB. The structure of fibrous proteins of the collagen‐gelatin group. Proc Natl Acad Sci U S A 37: 272‐281, 1951.
 406.Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99: 2750‐2756, 1999.
 407.Pawani H, Bhartiya D. Pluripotent stem cells for cardiac regeneration: Overview of recent advances & emerging trends. Indian J Med Res 137: 270‐282, 2013.
 408.Pearson‐White S. SnoI, a novel alternatively spliced isoform of the ski protooncogene homolog, sno. Nucleic Acids Res 21: 4632‐4638, 1993.
 409.Pedde RD, Mirani B, Navaei A, Styan T, Wong S, Mehrali M, Thakur A, Mohtaram NK, Bayati A, Dolatshahi‐Pirouz A, Nikkhah M, Willerth SM, Akbari M. Emerging biofabrication strategies for engineering complex tissue constructs. Adv Mater 29: 2017.
 410.Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70: 93‐104, 1992.
 411.Pelzer T, Lyons GE, Kim S, Moreadith RW. Cloning and characterization of the murine homolog of the sno proto‐oncogene reveals a novel splice variant. Dev Dyn 205: 114‐125, 1996.
 412.Pendleton C, Li Q, Chesler DA, Yuan K, Guerrero‐Cazares H, Quinones‐Hinojosa A. Mesenchymal stem cells derived from adipose tissue vs bone marrow: In vitro comparison of their tropism towards gliomas. PLoS One 8: e58198, 2013.
 413.Peng Y, Pan W, Ou Y, Xu W, Kaelber S, Borlongan CV, Sun M, Yu G. Extracardiac‐lodged mesenchymal stromal cells propel an inflammatory response against myocardial infarction via paracrine effects. Cell Transplant 25: 929‐935, 2016.
 414.Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD, Cardiovascular Cell Therapy Research N. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: The FOCUS‐CCTRN trial. JAMA 307: 1717‐1726, 2012.
 415.Pessah M, Marais J, Prunier C, Ferrand N, Lallemand F, Mauviel A, Atfi A. c‐Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. J Biol Chem 277: 29094‐29100, 2002.
 416.Petrov VV, Fagard RH, Lijnen PJ. Stimulation of collagen production by transforming growth factor‐beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension 39: 258‐263, 2002.
 417.Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, Kolls J, Riches DW, Deiuliis G, Kaminski N, Boregowda SV, McKenna DH, Ortiz LA. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 6: 8472, 2015.
 418.Piek A, de Boer RA, Sillje HH. The fibrosis‐cell death axis in heart failure. Heart Fail Rev 21: 199‐211, 2016.
 419.Pinali C, Bennett HJ, Davenport JB, Caldwell JL, Starborg T, Trafford AW, Kitmitto A. Three‐dimensional structure of the intercalated disc reveals plicate domain and gap junction remodeling in heart failure. Biophys J 108: 498‐507, 2015.
 420.Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 82: I103‐I113, 1990.
 421.Pok S, Myers JD, Madihally SV, Jacot JG. A multilayered scaffold of a chitosan and gelatin hydrogel supported by a PCL core for cardiac tissue engineering. Acta Biomater 9: 5630‐5642, 2013.
 422.Poncelet AC, de Caestecker MP, Schnaper HW. The transforming growth factor‐beta/SMAD signaling pathway is present and functional in human mesangial cells. Kidney Int 56: 1354‐1365, 1999.
 423.Poncelet AC, Schnaper HW. Sp1 and Smad proteins cooperate to mediate transforming growth factor‐beta 1‐induced alpha 2(I) collagen expression in human glomerular mesangial cells. J Biol Chem 276: 6983‐6992, 2001.
 424.Popovic AD, Neskovic AN, Pavlovski K, Marinkovic J, Babic R, Bojic M, Tan M, Thomas JD. Association of ventricular arrhythmias with left ventricular remodelling after myocardial infarction. Heart 77: 423‐427, 1997.
 425.Prathipati P, Metreveli N, Nandi SS, Tyagi SC, Mishra PK. Ablation of matrix metalloproteinase‐9 prevents cardiomyocytes contractile dysfunction in diabetics. Front Physiol 7: 93, 2016.
 426.Prockop DJ, Kivirikko KI. Collagens: Molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 64: 403‐434, 1995.
 427.Prunier C, Pessah M, Ferrand N, Seo SR, Howe P, Atfi A. The oncoprotein Ski acts as an antagonist of transforming growth factor‐beta signaling by suppressing Smad2 phosphorylation. J Biol Chem 278: 26249‐26257, 2003.
 428.Pryce BA, Brent AE, Murchison ND, Tabin CJ, Schweitzer R. Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn 236: 1677‐1682, 2007.
 429.Radhakumary C, Kumari TV, Kartha CC. Endomyocardial fibrosis is associated with selective deposition of type I collagen. Indian Heart J 53: 486‐489, 2001.
 430.Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, Dhama K. Oxidative stress, prooxidants, and antioxidants: The interplay. Biomed Res Int 2014: 761264, 2014.
 431.Rahimi Z. The role of renin Angiotensin aldosterone system genes in diabetic nephropathy. Can J Diabetes 40: 178‐183, 2016.
 432.Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ. MKK3‐ and MKK6‐regulated gene expression is mediated by the p38 mitogen‐activated protein kinase signal transduction pathway. Mol Cell Biol 16: 1247‐1255, 1996.
 433.Raizman JE, Komljenovic J, Chang R, Deng C, Bedosky KM, Rattan SG, Cunnington RH, Freed DH, Dixon IM. The participation of the Na+‐Ca2+ exchanger in primary cardiac myofibroblast migration, contraction, and proliferation. J Cell Physiol 213: 540‐551, 2007.
 434.Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10: 244‐258, 2012.
 435.Rao VU, Spinale FG. Controlling myocardial matrix remodeling: Implications for heart failure. Cardiol Rev 7: 136‐143, 1999.
 436.Redout EM, Wagner MJ, Zuidwijk MJ, Boer C, Musters RJ, van Hardeveld C, Paulus WJ, Simonides WS. Right‐ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. Cardiovasc Res 75: 770‐781, 2007.
 437.Reed JA, Lin Q, Chen D, Mian IS, Medrano EE. SKI pathways inducing progression of human melanoma. Cancer Metastasis Rev 24: 265‐272, 2005.
 438.Reis LA, Chiu LL, Liang Y, Hyunh K, Momen A, Radisic M. A peptide‐modified chitosan–collagen hydrogel for cardiac cell culture and delivery. Acta Biomater 8: 1022‐1036, 2012.
 439.Respress JL, van Oort RJ, Li N, Rolim N, Dixit SS, deAlmeida A, Voigt N, Lawrence WS, Skapura DG, Skardal K, Wisloff U, Wieland T, Ai X, Pogwizd SM, Dobrev D, Wehrens XH. Role of RyR2 phosphorylation at S2814 during heart failure progression. Circ Res 110: 1474‐1483, 2012.
 440.Ricard‐Blum S, Salza R. Matricryptins and matrikines: Biologically active fragments of the extracellular matrix. Exp Dermatol 23: 457‐463, 2014.
 441.Rienks M, Carai P, Bitsch N, Schellings M, Vanhaverbeke M, Verjans J, Cuijpers I, Heymans S, Papageorgiou A. Sema3A promotes the resolution of cardiac inflammation after myocardial infarction. Basic Res Cardiol 112: 42, 2017.
 442.Rienks M, Papageorgiou AP, Frangogiannis NG, Heymans S. Myocardial extracellular matrix: An ever‐changing and diverse entity. Circ Res 114: 872‐888, 2014.
 443.Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1+/− haploinsufficient mice. Circulation 112: 2959‐2965, 2005.
 444.Ritter M, Kattmann D, Teichler S, Hartmann O, Samuelsson MK, Burchert A, Bach JP, Kim TD, Berwanger B, Thiede C, Jager R, Ehninger G, Schafer H, Ueki N, Hayman MJ, Eilers M, Neubauer A. Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia. Leukemia 20: 437‐443, 2006.
 445.Roche PL, Filomeno KL, Bagchi RA, Czubryt MP. Intracellular signaling of cardiac fibroblasts. Compr Physiol 5: 721‐760, 2015.
 446.Rodriguez‐Iturbe B, Sepassi L, Quiroz Y, Ni Z, Wallace DC, Vaziri ND. Association of mitochondrial SOD deficiency with salt‐sensitive hypertension and accelerated renal senescence. J Appl Physiol (1985) 102: 255‐260, 2007.
 447.Rodriguez ER, Tan CD. Structure and anatomy of the human pericardium. Prog Cardiovasc Dis 59: 327‐340, 2017.
 448.Roger VL. Epidemiology of heart failure. Circ Res 113: 646‐659, 2013.
 449.Roger VL, Go AS, Lloyd‐Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics C, Stroke Statistics S. Executive summary: Heart disease and stroke statistics–2012 update: A report from the American Heart Association. Circulation 125: 188‐197, 2012.
 450.Roger VL, Go AS, Lloyd‐Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics C, Stroke Statistics S. Heart disease and stroke statistics–2012 update: A report from the American Heart Association. Circulation 125: e2‐e220, 2012.
 451.Rosin NL, Sopel M, Falkenham A, Myers TL, Legare JF. Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis. Hypertens Res 35: 449‐456, 2012.
 452.Ross RS, Borg TK. Integrins and the myocardium. Circ Res 88: 1112‐1119, 2001.
 453.Runyan CE, Schnaper HW, Poncelet AC. The phosphatidylinositol 3‐kinase/Akt pathway enhances Smad3‐stimulated mesangial cell collagen I expression in response to transforming growth factor‐beta1. J Biol Chem 279: 2632‐2639, 2004.
 454.Ruvinov E, Leor J, Cohen S. The promotion of myocardial repair by the sequential delivery of IGF‐1 and HGF from an injectable alginate biomaterial in a model of acute myocardial infarction. Biomaterials 32: 565‐578., 2011.
 455.Sadoshima J, Izumo S. Tyrosine kinases mediation of c‐fos expression by cell swelling in cardiac myocytes. Heart Vessels (Suppl 12): 194‐197, 1997.
 456.Sag CM, Wadsack DP, Khabbazzadeh S, Abesser M, Grefe C, Neumann K, Opiela MK, Backs J, Olson EN, Brown JH, Neef S, Maier SK, Maier LS. Calcium/calmodulin‐dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circ Heart Fail 2: 664‐675, 2009.
 457.Sakamuri SS, Takawale A, Basu R, Fedak PW, Freed D, Sergi C, Oudit GY, Kassiri Z. Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. Transl Res 172: 30‐44, 2016.
 458.Samuel CS, Summers RJ, Hewitson TD. Antifibrotic actions of serelaxin–‐new roles for an old player. Trends Pharmacol Sci 37: 485‐497, 2016.
 459.Sansbury BE, Spite M. Resolution of acute inflammation and the role of resolvins in immunity, thrombosis, and vascular biology. Circ Res 119: 113‐130, 2016.
 460.Santiago JJ, Dangerfield AL, Rattan SG, Bathe KL, Cunnington RH, Raizman JE, Bedosky KM, Freed DH, Kardami E, Dixon IM. Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: Expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Dev Dyn 239: 1573‐1584, 2010.
 461.Santini MP, Rosenthal N. Myocardial regenerative properties of macrophage populations and stem cells. J Cardiovasc Transl Res 5: 700‐712, 2012.
 462.Sarrazy V, Koehler A, Chow ML, Zimina E, Li CX, Kato H, Caldarone CA, Hinz B. Integrins alphavbeta5 and alphavbeta3 promote latent TGF‐beta1 activation by human cardiac fibroblast contraction. Cardiovasc Res 102: 407‐417, 2014.
 463.Sawicki G. Synergistic effect of inhibitors of MMPs and ROS‐dependent modifications of contractile proteins on protection hearts subjected to oxidative stress. Curr Pharm Des 20: 1345‐1348, 2014.
 464.Schepers D, Doyle AJ, Oswald G, Sparks E, Myers L, Willems PJ, Mansour S, Simpson MA, Frysira H, Maat‐Kievit A, Van Minkelen R, Hoogeboom JM, Mortier GR, Titheradge H, Brueton L, Starr L, Stark Z, Ockeloen C, Lourenco CM, Blair E, Hobson E, Hurst J, Maystadt I, Destree A, Girisha KM, Miller M, Dietz HC, Loeys B, Van Laer L. The SMAD‐binding domain of SKI: A hotspot for de novo mutations causing Shprintzen‐Goldberg syndrome. Eur J Hum Genet 23: 224‐228, 2015.
 465.Schinkothe T, Bloch W, Schmidt A. In vitro secreting profile of human mesenchymal stem cells. Stem Cells Dev 17: 199‐206, 2008.
 466.Scholkmann F. Long range physical cell‐to‐cell signalling via mitochondria inside membrane nanotubes: A hypothesis. Theor Biol Med Model 13: 16, 2016.
 467.Schonherr E, Hausser HJ. Extracellular matrix and cytokines: A functional unit. Dev Immunol 7: 89‐101, 2000.
 468.Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128: 3855‐3866, 2001.
 469.Sedger LM, McDermott MF. TNF and TNF‐receptors: From mediators of cell death and inflammation to therapeutic giants ‐ past, present and future. Cytokine Growth Factor Rev 25: 453‐472, 2014.
 470.Seidel T, Navankasattusas S, Ahmad AA, Diakos NA, Xu WD, Tristani‐Firouzi M, Bonios M, Taleb I, Li DY, Selzman CH. Sheet‐like remodeling of the transverse tubular system in human heart failure impairs excitation‐contraction coupling and functional recovery by mechanical unloading. Circulation 135: 1632‐1645, 2017.
 471.Sequiera GL, Saravanan S, Dhingra S. Human‐induced pluripotent stem cell‐derived mesenchymal stem cells as an individual‐specific and renewable source of adult stem cells. Methods Mol Biol 1553: 183‐190, 2017.
 472.Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: Dual anti‐inflammatory and pro‐resolution lipid mediators. Nat Rev Immunol 8: 349‐361, 2008.
 473.Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N. Protectins and maresins: New pro‐resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim Biophys Acta 1851: 397‐413, 2015.
 474.Serini G, Bochaton‐Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G. The fibronectin domain ED‐A is crucial for myofibroblastic phenotype induction by transforming growth factor‐beta1. J Cell Biol 142: 873‐881, 1998.
 475.Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250: 273‐283, 1999.
 476.Sesso HD, Lee IM, Gaziano JM, Rexrode KM, Glynn RJ, Buring JE. Maternal and paternal history of myocardial infarction and risk of cardiovascular disease in men and women. Circulation 104: 393‐398, 2001.
 477.Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: The cytokine hypothesis. J Card Fail 2: 243‐249, 1996.
 478.Shaikh FM, Callanan A, Kavanagh EG, Burke PE, Grace PA, McGloughlin TM. Fibrin: A natural biodegradable scaffold in vascular tissue engineering. Cells Tissues Organs 188: 333‐346, 2008.
 479.Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T, Okada K, Shiba N, Sakamoto K, Ido D, Shiina T, Ohkura M, Nakai J, Uno N, Kazuki Y, Oshimura M, Minami I, Ikeda U. Allogeneic transplantation of iPS cell‐derived cardiomyocytes regenerates primate hearts. Nature 538: 388‐391, 2016.
 480.Shin SR, Jung SM, Zalabany M, Kim K, Zorlutuna P, Kim Sb, Nikkhah M, Khabiry M, Azize M, Kong J, Wan K‐t, Palacios T, Dokmeci MR, Bae H, Tang XS, Khademhosseini A. Carbon‐nanotube‐embedded hydrogel sheets for engineering cardiac constructs and bioactuators. ACS Nano 7: 2369‐2380, 2013.
 481.Shin SR, Li YC, Jang HL, Khoshakhlagh P, Akbari M, Nasajpour A, Zhang YS, Tamayol A, Khademhosseini A. Graphene‐based materials for tissue engineering. Adv Drug Deliv Rev 105: 255‐274, 2016.
 482.Shin SR, Zihlmann C, Akbari M, Assawes P, Cheung L, Zhang K, Manoharan V, Zhang YS, Yüksekkaya M, Wan Kt. Reduced graphene oxide‐GelMA hybrid hydrogels as scaffolds for cardiac tissue engineering. Small 12: 3677‐3687, 2016.
 483.Shin SR, Zihlmann C, Akbari M, Assawes P, Cheung L, Zhang K, Manoharan V, Zhang YS, Yuksekkaya M, Wan KT, Nikkhah M, Dokmeci MR, Tang XS, Khademhosseini A. Reduced graphene oxide‐GelMA hybrid hydrogels as scaffolds for cardiac tissue engineering. Small 12: 3677‐3689, 2016.
 484.Shprintzen RJ, Goldberg RB. A recurrent pattern syndrome of craniosynostosis associated with arachnodactyly and abdominal hernias. J Craniofac Genet Dev Biol 2: 65‐74, 1982.
 485.Shu Y, Hao T, Yao F, Qian Y, Wang Y, Yang B, Li J, Wang C. RoY peptide‐modified chitosan‐based hydrogel to improve angiogenesis and cardiac repair under hypoxia. ACS Appl Mater Interfaces 7: 6505‐6517, 2015.
 486.Shukunami C, Takimoto A, Oro M, Hiraki Y. Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol 298: 234‐247, 2006.
 487.Simioniuc A, Carluccio E, Ghio S, Rossi A, Biagioli P, Reboldi G, Galeotti GG, Lu F, Zara C, Whalley G. Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients. Int J Cardiol 224: 416‐423, 2016.
 488.Simoes e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin‐(1‐7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol 169: 477‐492, 2013.
 489.Sinagra E, Perricone G, Romano C, Cottone M. Heart failure and anti tumor necrosis factor‐alpha in systemic chronic inflammatory diseases. Eur J Intern Med 24: 385‐392, 2013.
 490.Singh KD, Karnik SS. Angiotensin receptors: Structure, function, signaling and clinical applications. J Cell Signal 1: pii: 111, 2016.
 491.Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280: C53‐C60, 2001.
 492.Slomka T, Lennon ES, Akbar H, Gosmanova EO, Bhattacharya SK, Oliphant CS, Khouzam RN. Effects of renin‐angiotensin‐aldosterone system blockade in patients with end‐stage renal disease. Am J Med Sci 351: 309‐316, 2016.
 493.Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K, Olson EN. Myocardin‐related transcription factor‐a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res 107: 294‐304, 2010.
 494.Smith‐Mungo LI, Kagan HM. Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biol 16: 387‐398, 1998.
 495.Solaro RJ, Rarick HM. Troponin and tropomyosin: Proteins that switch on and tune in the activity of cardiac myofilaments. Circ Res 83: 471‐480, 1998.
 496.Solomon SD, Claggett B, Desai AS, Packer M, Zile M, Swedberg K, Rouleau JL, Shi VC, Starling RC, Kozan Ö. Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM‐HF) Trial. Circ Heart Fail 9: e002744, 2016.
 497.Song R, Li G, Li S. Aspidin PB, a novel natural anti‐fibrotic compound, inhibited fibrogenesis in TGF‐beta1‐stimulated keloid fibroblasts via PI‐3 K/Akt and Smad signaling pathways. Chem Biol Interact 238: 66‐73, 2015.
 498.Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin‐1 and the Marfanoid‐craniosynostosis (Shprintzen‐Goldberg) syndrome. Nat Genet 12: 209‐211, 1996.
 499.Sopel M, Falkenham A, Oxner A, Ma I, Lee TD, Legare JF. Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis. Int J Exp Pathol 93: 115‐124, 2012.
 500.Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 8: 132‐140, 2002.
 501.Sotiropoulos A, Gineitis D, Copeland J, Treisman R. Signal‐regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98: 159‐169, 1999.
 502.Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: The renaissance cell. Circ Res 105: 1164‐1176, 2009.
 503.Spicer DE, Bridgeman JM, Brown NA, Mohun TJ, Anderson RH. The anatomy and development of the cardiac valves. Cardiol Young 24: 1008‐1022, 2014.
 504.Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time‐dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: Relation to ventricular and myocyte function. Circ Res 82: 482‐495, 1998.
 505.Srivastava D, Cserjesi P, Olson EN. A subclass of bHLH proteins required for cardiac morphogenesis. Science 270: 1995‐1999, 1995.
 506.St John Sutton M, Lee D, Rouleau JL, Goldman S, Plappert T, Braunwald E, Pfeffer MA. Left ventricular remodeling and ventricular arrhythmias after myocardial infarction. Circulation 107: 2577‐2582, 2003.
 507.Standring S. Gray's Anatomy: The Anatomical Basis of Clinical Practice. New York: Elsevier Limited, 2016.
 508.Staniek K, Nohl H. H(2)O(2) detection from intact mitochondria as a measure for one‐electron reduction of dioxygen requires a non‐invasive assay system. Biochim Biophys Acta 1413: 70‐80, 1999.
 509.Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr Opin Pharmacol 23: 82‐91, 2015.
 510.Stavnezer E, Gerhard DS, Binari RC, Balazs I. Generation of transforming viruses in cultures of chicken fibroblasts infected with an avian leukosis virus. J Virol 39: 920‐934, 1981.
 511.Stoppel WL, Hu D, Domian IJ, Kaplan DL, III LDB. Anisotropic silk biomaterials containing cardiac extracellular matrix for cardiac tissue engineering. Biomed Mater 10: 034105., 2015.
 512.Stout DA, Basu B, Webster TJ. Poly(lactic–co‐glycolic acid): Carbon nanofiber composites for myocardial tissue engineering applications. Acta Biomater 7: 3101‐3112, 2011.
 513.Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF‐beta signaling by the SnoN oncoprotein. Science 286: 771‐774, 1999.
 514.Sturk A, Hack CE, Aarden LA, Brouwer M, Koster RR, Sanders GT. Interleukin‐6 release and the acute‐phase reaction in patients with acute myocardial infarction: A pilot study. J Lab Clin Med 119: 574‐579, 1992.
 515.Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A. Oxidative stress mediates tumor necrosis factor‐alpha‐induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107: 1418‐1423, 2003.
 516.Sun Y. Local angiotensin II and myocardial fibrosis. Adv Exp Med Biol 432: 55‐61, 1997.
 517.Suncion VY, Ghersin E, Fishman JE, Zambrano JP, Karantalis V, Mandel N, Nelson KH, Gerstenblith G, DiFede Velazquez DL, Breton E, Sitammagari K, Schulman IH, Taldone SN, Williams AR, Sanina C, Johnston PV, Brinker J, Altman P, Mushtaq M, Trachtenberg B, Mendizabal AM, Tracy M, Da Silva J, McNiece IK, Lardo AC, George RT, Hare JM, Heldman AW. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res 114: 1292‐1301, 2014.
 518.Sutrave P, Copeland TD, Showalter SD, Hughes SH. Characterization of chicken c‐ski oncogene products expressed by retrovirus vectors. Mol Cell Biol 10: 3137‐3144, 1990.
 519.Sutrave P, Hughes SH. Isolation and characterization of three distinct cDNAs for the chicken c‐ski gene. Mol Cell Biol 9: 4046‐4051, 1989.
 520.Suzuki H, Yagi K, Kondo M, Kato M, Miyazono K, Miyazawa K. c‐Ski inhibits the TGF‐beta signaling pathway through stabilization of inactive Smad complexes on Smad‐binding elements. Oncogene 23: 5068‐5076, 2004.
 521.Suzuki K, Wilkes MC, Garamszegi N, Edens M, Leof EB. Transforming growth factor beta signaling via Ras in mesenchymal cells requires p21‐activated kinase 2 for extracellular signal‐regulated kinase‐dependent transcriptional responses. Cancer Res 67: 3673‐3682, 2007.
 522.Suzuki S, Shishido T, Funayama A, Netsu S, Ishino M, Kitahara T, Sasaki T, Katoh S, Otaki Y, Watanabe T, Shibata Y, Mantovani A, Takeishi Y, Kubota I. Long pentraxin PTX3 exacerbates pressure overload‐induced left ventricular dysfunction. PLoS One 8: e53133, 2013.
 523.Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, Wells A. Epidermal growth factor (EGF)‐like repeats of human tenascin‐C as ligands for EGF receptor. J Cell Biol 154: 459‐468, 2001.
 524.Taigen T, De Windt LJ, Lim HW, Molkentin JD. Targeted inhibition of calcineurin prevents agonist‐induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 97: 1196‐1201, 2000.
 525.Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z. Tissue inhibitor of matrix metalloproteinase‐1 promotes myocardial fibrosis by mediating CD63‐integrin beta1 interaction. Hypertension 69: 1092‐1103, 2017.
 526.Takeishi Y, Jalili T, Ball NA, Walsh RA. Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. Circ Res 85: 264‐271, 1999.
 527.Takezako T, Unal H, Karnik SS, Node K. Current topics in angiotensin II type 1 receptor research: Focus on inverse agonism, receptor dimerization and biased agonism. Pharmacol Res 123: 40‐50, 2017.
 528.Takimoto E. Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 115: 1221‐1231, 2005.
 529.Talan MI, Ahmet I, Xiao RP, Lakatta EG. beta(2) AR agonists in treatment of chronic heart failure: Long path to translation. J Mol Cell Cardiol 51: 529‐533. doi: 510.1016/j.yjmcc.2010.1009.1019. Epub 2010 Oct 1011., 2011.
 530.Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction‐from repair and remodeling to regeneration. Cell Tissue Res 365: 563‐581, 2016.
 531.Tamargo M, Tamargo J. Future drug discovery in renin‐angiotensin‐aldosterone system intervention. Expert Opin Drug Discov 12: 827‐848, 2017.
 532.Tan NS, Michalik L, Di‐Poi N, Desvergne B, Wahli W. Critical roles of the nuclear receptor PPARbeta (peroxisome‐proliferator‐activated receptor beta) in skin wound healing. Biochem Soc Trans 32: 97‐102, 2004.
 533.Tarapore P, Richmond C, Zheng G, Cohen SB, Kelder B, Kopchick J, Kruse U, Sippel AE, Colmenares C, Stavnezer E. DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI. Nucleic Acids Res 25: 3895‐3903, 1997.
 534.Tee R, Lokmic Z, Morrison WA, Dilley RJ. Strategies in cardiac tissue engineering. ANZ J Surg 80: 683‐693, 2010.
 535.Thavandiran N, Nunes SS, Xiao Y, Radisic M. Topological and electrical control of cardiac differentiation and assembly. Stem Cell Res Ther 4: 14, 2013.
 536.Thompson‐Gorman SL, Zweier JL. Evaluation of the role of xanthine oxidase in myocardial reperfusion injury. J Biol Chem 265: 6656‐6663, 1990.
 537.Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S. MicroRNA‐21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456: 980‐984, 2008.
 538.Tian Y, Pan D, Chordia MD, French BA, Kron IL, Yang Z. The spleen contributes importantly to myocardial infarct exacerbation during post‐ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE. Basic Res Cardiol 111: 62, 2016.
 539.Tibbles LA, Woodgett JR. The stress‐activated protein kinase pathways. Cell Mol Life Sci 55: 1230‐1254, 1999.
 540.Toback M. The role of cardiac remodeling in the progression of heart failure disease. In: Canadian Cardiovascular Congress Montreal, Quebec: 2016, p. s331.
 541.Toback M, Clark N. Strategies to improve self‐management in heart failure patients. Contemp Nurse 53: 105‐120, 2017.
 542.Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105: 93‐98, 2002.
 543.Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano‐regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3: 349‐363, 2002.
 544.Tucker WD, Bhimji SS. Anatomy, blood vessels. In: StatPearls. Treasure Island (FL): 2018.
 545.Turner NA, Porter KE. Function and fate of myofibroblasts after myocardial infarction. Fibrogenesis Tissue Repair 6: 5, 2013.
 546.Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 8: 726‐736, 2008.
 547.Ueki N, Hayman MJ. Direct interaction of Ski with either Smad3 or Smad4 is necessary and sufficient for Ski‐mediated repression of transforming growth factor‐beta signaling. J Biol Chem 278: 32489‐32492, 2003.
 548.Ueki N, Hayman MJ. Signal‐dependent N‐CoR requirement for repression by the Ski oncoprotein. J Biol Chem 278: 24858‐24864, 2003.
 549.Unger T, Paulis L, Sica DA. Therapeutic perspectives in hypertension: Novel means for renin‐angiotensin‐aldosterone system modulation and emerging device‐based approaches. Eur Heart J 32: 2739‐2747, 2011.
 550.van Amerongen MJ, Bou‐Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM, van Luyn MJ, Harmsen MC. Bone marrow‐derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol 214: 377‐386, 2008.
 551.van den Akker F, de Jager SC, Sluijter JP. Mesenchymal stem cell therapy for cardiac inflammation: immunomodulatory properties and the influence of toll‐like receptors. Mediators Inflamm 2013: 181020, 2013.
 552.van den Akker F, Deddens JC, Doevendans PA, Sluijter JP. Cardiac stem cell therapy to modulate inflammation upon myocardial infarction. Biochim Biophys Acta 1830: 2449‐2458, 2013.
 553.van der Geer P, Wiley S, Gish GD, Pawson T. The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein‐protein interactions. Curr Biol 6: 1435‐1444, 1996.
 554.van der Laan AM, Nahrendorf M, Piek JJ. Healing and adverse remodelling after acute myocardial infarction: Role of the cellular immune response. Heart 98: 1384‐1390, 2012.
 555.van Laake LW, Passier R, Monshouwer‐Kloots J, Verkleij AJ, Lips DJ, Freund C, den Ouden K, Ward‐van Oostwaard D, Korving J, Tertoolen LG, van Echteld CJ, Doevendans PA, Mummery CL. Human embryonic stem cell‐derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res 1: 9‐24, 2007.
 556.van Tuyn J, Atsma DE, Winter EM, van der Velde‐van Dijke I, Pijnappels DA, Bax NA, Knaan‐Shanzer S, Gittenberger‐de Groot AC, Poelmann RE, van der Laarse A, van der Wall EE, Schalij MJ, de Vries AA. Epicardial cells of human adults can undergo an epithelial‐to‐mesenchymal transition and obtain characteristics of smooth muscle cells in vitro. Stem Cells 25: 271‐278, 2007.
 557.Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc‐prolongation: systematic review of the evidence. Int J Clin Pharm 1‐10, 2016.
 558.Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH. BNIP3 and genetic control of necrosis‐like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20: 5454‐5468, 2000.
 559.Varkey M, Ding J, Tredget EE. Differential collagen‐glycosaminoglycan matrix remodeling by superficial and deep dermal fibroblasts: Potential therapeutic targets for hypertrophic scar. Biomaterials 32: 7581‐7591, 2011.
 560.Vassiliadis E, Barascuk N, Didangelos A, Karsdal MA. Novel cardiac‐specific biomarkers and the cardiovascular continuum. Biomark Insights 7: 45‐57, 2012.
 561.Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA. Protein kinases C and D mediate agonist‐dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol Cell Biol 24: 8374‐8385, 2004.
 562.Velez Rueda JO, Palomeque J, Mattiazzi A. Early apoptosis in different models of cardiac hypertrophy induced by high renin‐angiotensin system activity involves CaMKII. J Appl Physiol (1985) 112: 2110‐2120, 2012.
 563.Ventura‐Clapier R, Mettauer B, Bigard X. Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure. Cardiovasc Res 73: 10‐18, 2007.
 564.Vittal R, Fan L, Greenspan DS, Mickler EA, Gopalakrishnan B, Gu H, Benson HL, Zhang C, Burlingham W, Cummings OW, Wilkes DS. IL‐17 induces type V collagen overexpression and EMT via TGF‐beta‐dependent pathways in obliterative bronchiolitis. Am J Physiol Lung Cell Mol Physiol 304: L401‐L414, 2013.
 565.Voin V, Oskouian RJ, Loukas M, Tubbs RS. Auscultation of the heart: The basics with anatomical correlation. Clin Anat 30: 58‐60, 2017.
 566.Von Lueder TG, Sangaralingham SJ, Wang BH, Kompa AR, Atar D, Burnett JC, Krum H. Renin–angiotensin blockade combined with natriuretic peptide system augmentation novel therapeutic concepts to combat heart failure. Circ Heart Fail 6: 594‐605, 2013.
 567.Vunjak‐Novakovic G, Lui KO, Tandon N, Chien KR. Bioengineering heart muscle: A paradigm for regenerative medicine. Annu Rev Biomed Eng 13: 245‐267, 2011.
 568.Vunjak‐Novakovic G, Tandon N, Godier A, Maidhof R, Marsano A, Martens TP, Radisic M. Challenges in cardiac tissue engineering. Tissue Eng Part B Rev 16: 169‐187, 2010.
 569.Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol 282: H1685‐H1696, 2002.
 570.Wang B, Omar A, Angelovska T, Drobic V, Rattan SG, Jones SC, Dixon IM. Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts. Am J Physiol Heart Circ Physiol 293: H1282‐H1290, 2007.
 571.Wang H, Zhang X, Li Y, Ma Y, Zhang Y, Liu Z, Zhou J, Lin Q, Wang Y, Duan C, Wang C. Improved myocardial performance in infarcted rat heart by co‐injection of basic fibroblast growth factor with temperature‐responsive chitosan hydrogel. J Heart Lung Transplant 29: 881‐887, 2010.
 572.Wang J, Dodd C, Shankowsky HA, Scott PG, Tredget EE, Wound Healing Research G. Deep dermal fibroblasts contribute to hypertrophic scarring. Lab Invest 88: 1278‐1290, 2008.
 573.Wang L, Hou Y, Sun Y, Zhao L, Tang X, Hu P, Yang J, Zeng Z, Yang G, Cui X, Liu M. c‐Ski activates cancer‐associated fibroblasts to regulate breast cancer cell invasion. Mol Oncol 7: 1116‐1128, 2013.
 574.Wang X, Gerdes HH. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ 22: 1181‐1191, 2015.
 575.Weber KT. Cardiac interstitium in health and disease: The fibrillar collagen network. J Am Coll Cardiol 13: 1637‐1652, 1989.
 576.Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin‐angiotensin‐aldosterone system. Circulation 83: 1849‐1865, 1991.
 577.Weber KT, Jalil JE, Janicki JS, Pick R. Myocardial collagen remodeling in pressure overload hypertrophy. A case for interstitial heart disease. Am J Hypertens 2: 931‐940, 1989.
 578.Wei S, Chow LT, Shum IO, Qin L, Sanderson JE. Left and right ventricular collagen type I/III ratios and remodeling post‐myocardial infarction. J Card Fail 5: 117‐126, 1999.
 579.Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly‐derived cells. Stem Cells 26: 2865‐2874, 2008.
 580.Wen Z, Zheng S, Zhou C, Wang J, Wang T. Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction. J Cell Mol Med 15: 1032‐1043, 2011.
 581.Weng L, Wang W, Su X, Huang Y, Su L, Liu M, Sun Y, Yang B, Zhou H. The effect of cAMP‐PKA activation on TGF‐beta1‐induced profibrotic signaling. Cell Physiol Biochem 36: 1911‐1927, 2015.
 582.Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: Mechanisms and significance. Annu Rev Physiol 72: 19‐44, 2010.
 583.Widder J, Behr T, Fraccarollo D, Hu K, Galuppo P, Tas P, Angermann CE, Ertl G, Bauersachs J. Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase‐dependent. Cardiovasc Res 63: 161‐167, 2004.
 584.Wilkes MC, Mitchell H, Penheiter SG, Dore JJ, Suzuki K, Edens M, Sharma DK, Pagano RE, Leof EB. Transforming growth factor‐beta activation of phosphatidylinositol 3‐kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21‐activated kinase‐2. Cancer Res 65: 10431‐10440, 2005.
 585.Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd‐Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA 308: 1795‐1801, 2012.
 586.Willems IE, Havenith MG, De Mey JG, Daemen MJ. The alpha‐smooth muscle actin‐positive cells in healing human myocardial scars. Am J Pathol 145: 868‐875, 1994.
 587.Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hegde RS. Crystal structure of the dachshund homology domain of human SKI. Structure 12: 785‐792, 2004.
 588.Windak R, Muller J, Felley A, Akhmedov A, Wagner EF, Pedrazzini T, Sumara G, Ricci R. The AP‐1 transcription factor c‐Jun prevents stress‐imposed maladaptive remodeling of the heart. PLoS One 8: e73294, 2013.
 589.Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 ‐ an intimate relationship. Eur J Cell Biol 87: 601‐615, 2008.
 590.Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF‐beta1 from the extracellular matrix. J Cell Biol 179: 1311‐1323, 2007.
 591.Wolff G, Dimitroulis D, Andreotti F, Kolodziejczak M, Jung C, Scicchitano P, Devito F, Zito A, Occhipinti M, Castiglioni B, Calveri G, Maisano F, Ciccone MM, De Servi S, Navarese EP. Survival benefits of invasive versus conservative strategies in heart failure in patients with reduced ejection fraction and coronary artery disease: A meta‐analysis. Circ Heart Fail 10: pii: e003255, 2017.
 592.Wrighton KH, Liang M, Bryan B, Luo K, Liu M, Feng XH, Lin X. Transforming growth factor‐beta‐independent regulation of myogenesis by SnoN sumoylation. J Biol Chem 282: 6517‐6524, 2007.
 593.Wu JW, Krawitz AR, Chai J, Li W, Zhang F, Luo K, Shi Y. Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: Insights on Ski‐mediated repression of TGF‐beta signaling. Cell 111: 357‐367, 2002.
 594.Wu K, Yang Y, Wang C, Davoli MA, D'Amico M, Li A, Cveklova K, Kozmik Z, Lisanti MP, Russell RG, Cvekl A, Pestell RG. DACH1 inhibits transforming growth factor‐beta signaling through binding Smad4. J Biol Chem 278: 51673‐51684, 2003.
 595.Wu RC, Delgado D, Costigan J, Ross H, MacIver J. Pilot study of an Internet patient‐physician communication tool for heart failure disease management. World Hosp Health Serv 42: 32‐38, 2006.
 596.Wu X, Zhang T, Bossuyt J, Li X, McKinsey TA, Dedman JR, Olson EN, Chen J, Brown JH, Bers DM. Local InsP3‐dependent perinuclear Ca2+ signaling in cardiac myocyte excitation‐transcription coupling. J Clin Invest 116: 675‐682, 2006.
 597.Xiang MX, He AN, Wang JA, Gui C. Protective paracrine effect of mesenchymal stem cells on cardiomyocytes. J Zhejiang Univ Sci B 10: 619‐624, 2009.
 598.Xie M, Burchfield JS, Hill JA. Pathological ventricular remodeling: Therapies: Part 2 of 2. Circulation 128: 1021‐1030, 2013.
 599.Xie W, Zheng F, Song X, Zhong B, Yan L. Renin–angiotensin–aldosterone system blockers for heart failure with reduced ejection fraction or left ventricular dysfunction: Network meta‐analysis. Int J Cardiol 205: 65‐71, 2016.
 600.Xu W, Angelis K, Danielpour D, Haddad MM, Bischof O, Campisi J, Stavnezer E, Medrano EE. Ski acts as a co‐repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc Natl Acad Sci U S A 97: 5924‐5929, 2000.
 601.Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF‐beta signal transduction. Science 270: 2008‐2011, 1995.
 602.Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE. TRAF6 mediates Smad‐independent activation of JNK and p38 by TGF‐beta. Mol Cell 31: 918‐924, 2008.
 603.Yan C, Ding B, Shishido T, Woo CH, Itoh S, Jeon KI, Liu W, Xu H, McClain C, Molina CA, Blaxall BC, Abe J. Activation of extracellular signal‐regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. Circ Res 100: 510‐519, 2007.
 604.Yan C, Wang L, Li B, Zhang BB, Zhang B, Wang YH, Li XY, Chen JX, Tang RX, Zheng KY. The expression dynamics of transforming growth factor‐beta/Smad signaling in the liver fibrosis experimentally caused by Clonorchis sinensis. Parasit Vectors 8: 70, 2015.
 605.Yancy C, Jessup M, Bozkurt B, Butler J, Casey Jr D, Drazner M, Fonarow G, Geraci S, Horwich T, Januzzi J. ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 128: 1810‐1852, 2013.
 606.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128: 1810‐1852, 2013.
 607.Yang HW, Shin MG, Lee S, Kim JR, Park WS, Cho KH, Meyer T, Heo WD. Cooperative activation of PI3K by Ras and Rho family small GTPases. Mol Cell 47: 281‐290, 2012.
 608.Yang R, Chang L, Liu S, Jin X, Li Y. High glucose induces Rho/ROCK‐dependent visfatin and type I procollagen expression in rat primary cardiac fibroblasts. Mol Med Rep 10: 1992‐1998, 2014.
 609.Yeong WY, Sudarmadji N, Yu HY, Chua CK, Leong KF, Venkatraman SS, Boey YCF, Tan LP. Porous polycaprolactone scaffold for cardiac tissue engineering fabricated by selective laser sintering. Acta Biomater 6: 2028‐2034, 2010.
 610.Yin G, Yan C, Berk BC. Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35: 780‐783, 2003.
 611.Yoon SJ, Fang YH, Lim CH, Kim BS, Son HS, Park Y, Sun K. Regeneration of ischemic heart using hyaluronic acid‐based injectable hydrogel. J Biomed Mater Res B Appl Biomater 91: 163‐171, 2009.
 612.Young JL, Adam JE. Hydrogels with time‐dependent material properties enhance cardiomyocyte differentiation in vitro. Biomaterials 32: 1002‐1009, 2011.
 613.Yu J, Gu Y, Du KT, Mihardja S, Sievers RE, Lee RJ. The effect of injected RGD modified alginate on angiogenesis and left ventricular function in a chronic rat infarct model. Biomaterials 30: 751‐756, 2009.
 614.Yu L, Hebert MC, Zhang YE. TGF‐beta receptor‐activated p38 MAP kinase mediates Smad‐independent TGF‐beta responses. EMBO J 21: 3749‐3759, 2002.
 615.Yue P, Massie BM, Simpson PC, Long CS. Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol 275: H250‐H258, 1998.
 616.Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC, Aronow BJ, Lorenz JN, Dorn GW, II. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8: 725‐730, 2002.
 617.Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case‐control study. Lancet 364: 937‐952, 2004.
 618.Zeglinski MR, Hnatowich M, Jassal DS, Dixon IM. SnoN as a novel negative regulator of TGF‐beta/Smad signaling: A target for tailoring organ fibrosis. Am J Physiol Heart Circ Physiol 308: H75‐H82, 2015.
 619.Zeglinski MR, Roche P, Hnatowich M, Jassal DS, Wigle JT, Czubryt MP, Dixon IM. TGFbeta1 regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad‐independent mechanism. Am J Physiol Heart Circ Physiol 310: H239‐H249, 2016.
 620.Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial‐to‐mesenchymal transition contributes to cardiac fibrosis. Nat Med 13: 952‐961, 2007.
 621.Zhang L, Li L, Liu H, Borowitz JL, Isom GE. BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion. FASEB J 23: 3405‐3414, 2009.
 622.Zhang L, Liu C, Meng XM, Huang C, Xu F, Li J. Smad2 protects against TGF‐beta1/Smad3‐mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis. Mol Cell Biochem 400: 17‐28, 2015.
 623.Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, Jin TH, Desai L, Bernard K, Thannickal VJ. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest 123: 1096‐1108, 2013.
 624.Zimmerman MC. Angiotensin II and angiotensin‐1‐7 redox signaling in the central nervous system. Curr Opin Pharmacol 11: 138‐143, 2011.
 625.Zimmermann W‐H, Didié M, Wasmeier GH, Nixdorff U, Hess A, Melnychenko I, Boy O, Neuhuber WL, Weyand M, Eschenhagen T. Cardiac grafting of engineered heart tissue in syngenic rats. Circulation 106: I151‐I157, 2002.
 626.Zimmermann W‐H, Melnychenko I, Eschenhagen T. Engineered heart tissue for regeneration of diseased hearts. Biomaterials 25: 1639‐1647, 2004.

 

Teaching Material

Didactic Synopsis

Major Teaching Points:

Major teaching points of the current review include: (1) learning functional anatomy of the heart, which describe fundamental structural unit of the organ and its importance in understanding of HF concepts. (ii) Understanding role of RAAS (Renin-Angiotensin-Aldosterone System) in HF via regulation of the homeostasis of arterial pressure, fluid volume, heart perfusion, extracellular volume, the vascular response to injury, and inflammation. (iii) Getting deep knowledge on the role of adrenergic receptor signaling pathway in HF. (iv) Justifying how ROS is involved in HF signaling pathway. (v) Understanding the role of heart fibroblast and myofibroblast in heart fibrosis focusing on the importance of TGF-β1 canonical and noncanonical signaling in heart fibrosis and pathogenesis of heart HF. (vi) Potential therapeutic targets in HF including anti-inflammation therapy, antioxidant therapy and stem cell therapy (vii) Being familiar with concept of cardiac tissue engineering and repair in modern regenerative medicine.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Structural analysis of the heart to understand longitudinal and transverse section of the normal/healthy and remodeled heart.

Figure 2. Teaching points: A brief over view of the role RAAS, norepinephrine, and endothelin function in cardiac fibrosis and remodeling.

Figure 3. Teaching points: Dissecting survival (β2 AR) and apoptotic pathway (β1 AR) via Gs-cAMP-PKA-Akt and Gi-PI3K-AktGβγ in β2 AR ligation and activation of PKA-independent/CamKII-mediated apoptosis pathway via β1 AR ligation.

Figure 4. Teaching points: Concept of G-protein mediated signal transduction. After receptor ligation, G-Protein is activated via the exchange of GDP/GTP and induces Gα and Gβγ subunits dissociation. This is the concept of activation of small Rho-GTPase protein, initiation MAPK signaling, cAMP signaling, and activation of PLC-β.

Figure 5. Teaching points: The signaling pathway of adrenergic receptors in human cardiac tissue. The ligation of these receptors induces activation of two different pathways via AC and PLC effectors in human myocyte.

Figure 6. Teaching points: ROS is involved in pathological changes of the heart via three different pathways, including PKC and PKB, MAPK, and TNFα. Activation of these pathways induce cardiac remodeling, cardiomyocytes hypertrophy, and superoxide production.

Figure 7. Teaching points: Different phases of myocardial wound healing in post-MI patient has been descried. There are four different phases including Phase I (up to 8 h), Phase II (up to 6 days) Phase III (up to one month) and Phase IV (years after MI). The major event in Phase I is cardiomyocyte apoptosis and necrosis, Phase II involves acute inflammation, in Phase III granulated tissue is formed and finally in Phase IV scars are formed.

Figure 8. Teaching points: TGFβ1 noncanonical signaling involves Ras/ERK1/2, p38, PI3K, Rho A signaling.

Figure 9. Teaching point: The protein Structure of Ski (TGF-β1 transcriptional regulator) has been described. NH2 end of the protein plays a critical role in protein-protein interactions, and a R-Smad2/3 interacting domain that is important for Ski's ability to repress TGFβ/Smad-dependent signaling. The unique C2H2 (SAND) domain regulates interaction of Ski with Co-Smad4. The COOH terminal plays an important role in Ski:Sno homo- and hetero-dimerization as well as nuclear translocation of Ski [PRKRKLT – nuclear localization signal (NLS)].

Figure 10. Teaching points: Nuclear Ski can inhibit Smad-dependent signaling by (A) forming an inhibitory complex with the R-Smad/Co-Smad complex and stabilize them while bound to DNA. Ski can also repress TGFβ1/Smad signaling from the cytoplasm in two ways. First, (B) Ski can form a complex with the Smad complex and prevent nuclear translocation. Second (C) Ski can prevent R-Smad phosphorylation at the level of the TβRI and prevent R-Smad complex formation at the initiating step.

Figure 11. Teaching points: Ski and Scx form a negative feedback loop that regulates their gene expression. In the chronic post-MI setting, it is believed that this balance is tipped in favour of Scx, which promotes repression of Ski transcription leading to remodelling of the cardiac matrix. With TGFβ1 signaling unchecked by Ski, there is a significant increase in expression of fibrillar collagens and matrix proteins that ultimately cumulate to interstitial fibrosis and HF.

Figure 12. Teaching points: TGFβ1 is considered an inducer of Scx expression. TGFβ1 may exert its effects on Scx expression through a TGFβ1 noncanonical (p44/42 MAPK) signaling pathway in combination with c-Jun activation in cardiac myofibroblasts. Smad proteins may still be involved in regulating Scx through an alternative unknown mechanism through inhibition of p44/42.

Figure 13. Teaching points: Application of biomaterial science and regenerative medicine in cardiovascular tissue engineering. We have showed (A) effect of stretching of highly elastic scaffold made from MeTro shows the role of extensible MeTro molecule with an asymmetric coil and a C-terminal cell interactive motif in this process. (B) Testing the effect of torsion on MeTro-based hydrogels shows how this hydrogel change structure before (left) and after 27 rotations (right). (C) This is obvious there is no breakage in the hydrogel structure after twisting. Reprinted with permission from (18). Copyright 2015, WILEY-VCH Verlag GmbH & Co. (D) 5 days Culturing cardiac fibroblasts on random and aligned electrospun scaffold (gelatin:PGS blend) confirms the normal structural and cytoskeletal properties of fibroblasts. This observation was made based on fluorescent images for α-SMA (red), F-actin (green), and DAPI (blue). Reprinted with permission from (260). Copyright 2013, Elsevier.

 


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Matthew R. Zeglinski, Adel Rezaei Moghadam, Sudharsana R. Ande, Kimia Sheikholeslami, Pooneh Mokarram, Zahra Sepehri, Haleh Rokni, Nima Khadem Mohtaram, Mansour Poorebrahim, Anahita Masoom, Mehnosh Toback, Niketa Sareen, Sekaran Saravanan, Davinder S. Jassal, Mohammad Hashemi, Hassan Marzban, Dedmer Schaafsma, Pawan Singal, Jeffrey T. Wigle, Michael P. Czubryt, Mohsen Akbari, Ian M.C. Dixon, Saeid Ghavami, Joseph W. Gordon, Sanjiv Dhingra. Myocardial Cell Signaling During the Transition to Heart Failure. Compr Physiol 2018, 9: 75-125. doi: 10.1002/cphy.c170053