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Intracellular Signaling of Cardiac Fibroblasts

Patricia L. Roche, Krista L. Filomeno, Rushita A. Bagchi, Michael P. Czubryt

10.1002/cphy.c140044

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

Long regarded as a mere accessory cell for the cardiomyocyte, the cardiac fibroblast is now recognized as a critical determinant of cardiac function in health and disease. A recent renaissance in fibroblast‐centered research has fostered a better understanding than ever before of the biology of fibroblasts and their contractile counterparts, myofibroblasts. While advanced methodological approaches, including transgenics, lineage fate mapping, and improved cell marker identification have helped to facilitate this new work, the primary driver is arguably the contribution of myofibroblasts to cardiac pathophysiology including fibrosis and arrhythmogenesis. Fibrosis is a natural sequel to numerous common cardiac pathologies including myocardial infarction and hypertension, and typically exacerbates cardiovascular disease and progression to heart failure, yet no therapies currently exist to specifically target fibrosis. The regulatory processes and intracellular signaling pathways governing fibroblast and myofibroblast behavior thus represent important points of inquiry for the development of antifibrotic treatments. While steady progress is being made in uncovering the signaling pathways specific for cardiac fibroblast function (including proliferation, phenotype conversion, and matrix synthesis), much of what is currently known of fibroblast signaling mechanisms is derived from noncardiac fibroblast populations. Given the heterogeneity of fibroblasts across tissues, this dearth of information further underscores the need for progress in cardiac fibroblast biological research. © 2015 American Physiological Society. Compr Physiol 5:721‐760, 2015.

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Figure 1. Figure 1. Cardiac fibroblast activation and phenotype conversion. In the healthy myocardium, cardiac fibroblasts proliferate relatively slowly and maintain extracellular matrix homeostasis by continual synthesis of matrix constituents (e.g., collagens) and remodeling enzymes (e.g., matrix metalloproteinases/MMPs) at low basal levels. In response to stressors such as myocardial infarction, related proinflammatory and profibrotic cytokines, and/or increased matrix stiffness, cardiac fibroblasts become activated and initiate the wound healing process through matrix degradation (via increased expression of MMPs), proliferation, and migration to the site of injury, where they facilitate cardiac remodeling. In vitro work with fibroblasts has revealed a transient intermediate phenotype—the proto‐myofibroblast, which shares features of both fibroblasts and myofibroblasts. Proto‐myofibroblasts synthesize increased amounts of fibrillar collagens type I and III, and begin to express α‐smooth muscle actin (αSMA) and the ED‐A splice variant of fibronectin. Additionally, adhesions with the matrix are strengthened in proto‐myofibroblasts as are intracellular actin filaments, imparting contractility. As of yet, it remains unclear whether proto‐myofibroblasts exist as discrete entities in vivo. Fully phenotype converted cardiac myofibroblasts are characterized by reduced proliferation and migration, and in comparison to their precursors, are hypersynthetic for fibrillar collagens and other matrix components. Cardiac myofibroblasts also express increased levels of ED‐A fibronectin and αSMA, the latter of which is also incorporated into stress fibers that are stronger and thicker than their αSMA‐negative counterparts in proto‐myofibroblasts. In conjunction with these fibers, the maturation and strengthening of focal adhesions imparts greater contractile ability upon cardiac myofibroblasts. Contraction of surrounding scar tissue and collagen cross‐linking performed by myofibroblasts is necessary for scar maturation, though their persistence in the healed myocardium has also been implicated in the development of cardiac fibrosis.
Figure 2. Figure 2. Canonical transforming growth factor‐β (TGFβ) signaling and cardiac fibroblast gene expression. TGFβ is secreted by cardiac fibroblasts in an inactive form, bound noncovalently to latency‐associated peptide (LAP). LAP binds covalently to latent‐transforming growth factor‐β‐bound protein‐1 (LTBP‐1) within the normal extracellular matrix, and these three components form the large latent complex, or LLC. Increased tension within the matrix causes a conformational change in the LLC that allows rapid release and activation of TGFβ. Such forces can be transmitted to the LLC either indirectly (via increased fibronectin fibril extension within the matrix), directly (through LLC‐bound integrins on the surface of contractile myofibroblasts), or both. Active TGFβ can then bind to its receptor and induce heterotetramerization of TGFβ receptor subunits I and II. The serine/threonine kinase activity of TGFβ receptor subunit II is activated by ligand binding, in turn phosphorylating subunit I, which then phosphorylates receptor Smads 2 and 3 to allow recruitment of co‐Smads such as Smad4. The Smad complex then translocates into the nucleus to activate transcription of target genes such as αSMA and fibrillar collagens. The transcription factor Ski attenuates this process in cardiac myofibroblasts, abrogating phenotype conversion. TGFβ‐activated Smad3 increases expression of the transcription factor scleraxis (Scx), which acts synergistically with Smad3 to transactivate the collagen 1α2 gene. TGFβ receptor activation also activates a negative feedback loop via the expression of inhibitory Smad7, which suppresses Scx expression and forms a complex with Smurf in the nucleus that translocates to the cytoplasm to repress phosphorylation and activation of receptor Smads.
Figure 3. Figure 3. Mechanosensing through integrins. Integrin activation and downstream signaling occurs in response to both outside‐in and inside‐out signaling, both of which evoke conformational changes in integrin structure. The inside‐out pathway involves binding of talin to the β‐integrin NXPY motif. Various mechanisms have been proposed in the regulation of talin binding‐mediated integrin activation through competing factors such as the Src‐family kinase (SFK)‐activated docking protein 1 (Dok1), among others. Outside‐in signaling requires interaction of extracellular matrix (ECM) ligands with integrins, a mechanism that is sensitive to the degree of extracellular tension or force. Ligands expressed by cardiac fibroblasts and found in the ECM include fibronectin (FN), osteopontin (OPN), and vitronectin (VTN). Similar to inside‐out signaling, recruitment of talin to integrins is a key step. Putative candidates in talin recruitment in cardiac fibroblasts include focal adhesion kinase (FAK) and Rap1‐GTP‐interacting adaptor molecule (RIAM) downstream of Rap1 activation. Force‐activated integrins mediate phosphorylation of SFK and FAK, the latter of which forms a complex linking the mechanosensory protein p130Cas to Wiskott‐Aldrich Syndrome protein (WASP) and cytoskeletal F‐actin filaments. Force‐induced FAK activation upregulates the small GTPase RhoA, activating downstream mammalian diaphanous‐1 (mDia1) and Rho‐associated kinase (ROCK), inducing subsequent actin filament polymerization and myosin II‐mediated contraction. ROCK activation also induces the release of myocardin‐related transcription factor‐A (MRTF‐A), which forms a complex with serum response factor (SRF) and directly activates α‐smooth muscle actin (αSMA) transcription. Activation of FAK and SFK also results in downstream activation of the Ras‐Raf‐MAPK‐ERK pathway, inducing SRF activation, which in turn activates the transcription factor Sap to upregulate downstream target genes.
Figure 4. Figure 4. Signaling pathways governing cardiac fibroblast migration. Fibroblast migration requires both intracellular actin remodeling to drive motility, and the extracellular release of remodeling enzymes to facilitate cell movement through the surrounding stroma. A host of extracellular ligands act on cardiac fibroblasts to induce migration, acting via distinct pathways to govern both activities. Adipocyte‐released cytokines leptin and adiponectin act on their respective receptors in cardiac fibroblasts to induce migration. Leptin‐induced signaling activates the RhoA‐Rho‐GTPase‐associated kinase (ROCK)‐cofilin pathway. Cofilin severs actin filaments, inducing actin remodeling and reducing F‐actin content. Leptin signaling also causes activation and relocation of type‐I transmembrane matrix metalloproteinase (MT1‐MMP) to the cell surface, where it can cleave and activate pro‐MMP2, causing degradation of extracellular matrix components and increased migration. Adiponectin also activates MT1‐MMP downstream of the adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing‐1 (APPL1)‐AMP‐activated protein kinase (AMPK) signaling cascade. Binding of angiotensin II (AngII) and interleukin‐8 and ‐18 to their respective transmembrane receptors causes activation of NADPH oxidase‐4 (Nox4), resulting in increased reactive oxygen species (ROS) production. AngII‐induced ROS production activates the transcription factors Nuclear Factor κB (NF‐κB), activator protein‐1 (AP‐1), and specificity protein‐1 (Sp1) through extracellular signal‐regulated kinase (ERK) signaling. Through this pathway, NF‐κB and AP‐1 induce activation of various MMPs, and both Sp1 and AP‐1 repress activity of the adhesion protein reversion‐inducing‐cysteine‐rich protein with kazal motifs (RECK). Thus, AngII signaling induces cardiac fibroblast migration by increasing matrix degradation and reducing cell adhesion. Interleukin‐8 and ‐18 also utilize Nox4‐ROS signaling, but with a tumor necrosis factor receptor‐associated‐3‐interacting protein‐2 (TRAF3IP2) intermediate. Activation of AP‐1 and NF‐κB downstream of these interleukins induces MMP activity, increasing cardiac fibroblast migration. It is likely that additional pathways identified in noncardiac fibroblasts are also involved in cardiac fibroblast migration, however they remain to be characterized.
Figure 5. Figure 5. Akt‐mediated regulation of cardiac fibroblast proliferation. Growth factors such as PDGF and FGF bind to their cognate receptors, resulting in associated receptor tyrosine kinase (RTK) activation. Upon ligand binding, PI3K subunits p85 and p110 are recruited to the receptor to form the activated PI3K enzyme, catalyzing the conversion of PIP2 to PIP3. PIP3 recruits Akt to the plasma membrane, where it is phosphorylated by PDK1 thereby promoting its translocation into the nucleus. p70S6 Kinase is activated downstream of phospho‐Akt and in turn phosphorylates the S6 protein within the 40S ribosomal subunit, positively regulating cell growth and proliferation. Phospho‐Akt further promotes cell proliferation by phosphorylating and thereby deactivating GSK3. GSK3 flags Cyclin D1 for translocation into the cytoplasm of the cell, make it unavailable to regulate the cell cycle and resulting in cell‐cycle arrest.
Figure 6. Figure 6. Myofibroblast contractile response. Contraction of stress fibers occurs via calcium‐dependent and ‐independent signaling pathways in cardiac fibroblasts. Calcium‐dependent contraction is typically rapid and occurs primarily in peripheral stress fibers. Through receptors such as transient receptor potential cation (TRPC) channels, calcium‐dependent contraction occurs in response to an influx of Ca2+ ions, which form a complex with and activate calmodulin, resulting in myosin light chain kinase (MLCK) activation and subsequent phosphorylation of myosin light chain (MLC) bound to stress fibers. However, contraction is not sustained due to the activity of myosin phosphatase (MP) within the cell, which dephosphorylates and inactivates actin‐bound MLC. Conversely, calcium‐independent contraction is relatively slow and acts primarily on central stress fibers in sustained contractile events, usually in response to mechanical strain. Calcium‐independent contraction occurs primarily through integrin activation and downstream RhoA‐Rho‐GTPase‐associated kinase (ROCK) signaling, which inhibits MP to maintain phosphorylation of MLC, allowing for prolonged contractile events.


Figure 1. Cardiac fibroblast activation and phenotype conversion. In the healthy myocardium, cardiac fibroblasts proliferate relatively slowly and maintain extracellular matrix homeostasis by continual synthesis of matrix constituents (e.g., collagens) and remodeling enzymes (e.g., matrix metalloproteinases/MMPs) at low basal levels. In response to stressors such as myocardial infarction, related proinflammatory and profibrotic cytokines, and/or increased matrix stiffness, cardiac fibroblasts become activated and initiate the wound healing process through matrix degradation (via increased expression of MMPs), proliferation, and migration to the site of injury, where they facilitate cardiac remodeling. In vitro work with fibroblasts has revealed a transient intermediate phenotype—the proto‐myofibroblast, which shares features of both fibroblasts and myofibroblasts. Proto‐myofibroblasts synthesize increased amounts of fibrillar collagens type I and III, and begin to express α‐smooth muscle actin (αSMA) and the ED‐A splice variant of fibronectin. Additionally, adhesions with the matrix are strengthened in proto‐myofibroblasts as are intracellular actin filaments, imparting contractility. As of yet, it remains unclear whether proto‐myofibroblasts exist as discrete entities in vivo. Fully phenotype converted cardiac myofibroblasts are characterized by reduced proliferation and migration, and in comparison to their precursors, are hypersynthetic for fibrillar collagens and other matrix components. Cardiac myofibroblasts also express increased levels of ED‐A fibronectin and αSMA, the latter of which is also incorporated into stress fibers that are stronger and thicker than their αSMA‐negative counterparts in proto‐myofibroblasts. In conjunction with these fibers, the maturation and strengthening of focal adhesions imparts greater contractile ability upon cardiac myofibroblasts. Contraction of surrounding scar tissue and collagen cross‐linking performed by myofibroblasts is necessary for scar maturation, though their persistence in the healed myocardium has also been implicated in the development of cardiac fibrosis.


Figure 2. Canonical transforming growth factor‐β (TGFβ) signaling and cardiac fibroblast gene expression. TGFβ is secreted by cardiac fibroblasts in an inactive form, bound noncovalently to latency‐associated peptide (LAP). LAP binds covalently to latent‐transforming growth factor‐β‐bound protein‐1 (LTBP‐1) within the normal extracellular matrix, and these three components form the large latent complex, or LLC. Increased tension within the matrix causes a conformational change in the LLC that allows rapid release and activation of TGFβ. Such forces can be transmitted to the LLC either indirectly (via increased fibronectin fibril extension within the matrix), directly (through LLC‐bound integrins on the surface of contractile myofibroblasts), or both. Active TGFβ can then bind to its receptor and induce heterotetramerization of TGFβ receptor subunits I and II. The serine/threonine kinase activity of TGFβ receptor subunit II is activated by ligand binding, in turn phosphorylating subunit I, which then phosphorylates receptor Smads 2 and 3 to allow recruitment of co‐Smads such as Smad4. The Smad complex then translocates into the nucleus to activate transcription of target genes such as αSMA and fibrillar collagens. The transcription factor Ski attenuates this process in cardiac myofibroblasts, abrogating phenotype conversion. TGFβ‐activated Smad3 increases expression of the transcription factor scleraxis (Scx), which acts synergistically with Smad3 to transactivate the collagen 1α2 gene. TGFβ receptor activation also activates a negative feedback loop via the expression of inhibitory Smad7, which suppresses Scx expression and forms a complex with Smurf in the nucleus that translocates to the cytoplasm to repress phosphorylation and activation of receptor Smads.


Figure 3. Mechanosensing through integrins. Integrin activation and downstream signaling occurs in response to both outside‐in and inside‐out signaling, both of which evoke conformational changes in integrin structure. The inside‐out pathway involves binding of talin to the β‐integrin NXPY motif. Various mechanisms have been proposed in the regulation of talin binding‐mediated integrin activation through competing factors such as the Src‐family kinase (SFK)‐activated docking protein 1 (Dok1), among others. Outside‐in signaling requires interaction of extracellular matrix (ECM) ligands with integrins, a mechanism that is sensitive to the degree of extracellular tension or force. Ligands expressed by cardiac fibroblasts and found in the ECM include fibronectin (FN), osteopontin (OPN), and vitronectin (VTN). Similar to inside‐out signaling, recruitment of talin to integrins is a key step. Putative candidates in talin recruitment in cardiac fibroblasts include focal adhesion kinase (FAK) and Rap1‐GTP‐interacting adaptor molecule (RIAM) downstream of Rap1 activation. Force‐activated integrins mediate phosphorylation of SFK and FAK, the latter of which forms a complex linking the mechanosensory protein p130Cas to Wiskott‐Aldrich Syndrome protein (WASP) and cytoskeletal F‐actin filaments. Force‐induced FAK activation upregulates the small GTPase RhoA, activating downstream mammalian diaphanous‐1 (mDia1) and Rho‐associated kinase (ROCK), inducing subsequent actin filament polymerization and myosin II‐mediated contraction. ROCK activation also induces the release of myocardin‐related transcription factor‐A (MRTF‐A), which forms a complex with serum response factor (SRF) and directly activates α‐smooth muscle actin (αSMA) transcription. Activation of FAK and SFK also results in downstream activation of the Ras‐Raf‐MAPK‐ERK pathway, inducing SRF activation, which in turn activates the transcription factor Sap to upregulate downstream target genes.


Figure 4. Signaling pathways governing cardiac fibroblast migration. Fibroblast migration requires both intracellular actin remodeling to drive motility, and the extracellular release of remodeling enzymes to facilitate cell movement through the surrounding stroma. A host of extracellular ligands act on cardiac fibroblasts to induce migration, acting via distinct pathways to govern both activities. Adipocyte‐released cytokines leptin and adiponectin act on their respective receptors in cardiac fibroblasts to induce migration. Leptin‐induced signaling activates the RhoA‐Rho‐GTPase‐associated kinase (ROCK)‐cofilin pathway. Cofilin severs actin filaments, inducing actin remodeling and reducing F‐actin content. Leptin signaling also causes activation and relocation of type‐I transmembrane matrix metalloproteinase (MT1‐MMP) to the cell surface, where it can cleave and activate pro‐MMP2, causing degradation of extracellular matrix components and increased migration. Adiponectin also activates MT1‐MMP downstream of the adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing‐1 (APPL1)‐AMP‐activated protein kinase (AMPK) signaling cascade. Binding of angiotensin II (AngII) and interleukin‐8 and ‐18 to their respective transmembrane receptors causes activation of NADPH oxidase‐4 (Nox4), resulting in increased reactive oxygen species (ROS) production. AngII‐induced ROS production activates the transcription factors Nuclear Factor κB (NF‐κB), activator protein‐1 (AP‐1), and specificity protein‐1 (Sp1) through extracellular signal‐regulated kinase (ERK) signaling. Through this pathway, NF‐κB and AP‐1 induce activation of various MMPs, and both Sp1 and AP‐1 repress activity of the adhesion protein reversion‐inducing‐cysteine‐rich protein with kazal motifs (RECK). Thus, AngII signaling induces cardiac fibroblast migration by increasing matrix degradation and reducing cell adhesion. Interleukin‐8 and ‐18 also utilize Nox4‐ROS signaling, but with a tumor necrosis factor receptor‐associated‐3‐interacting protein‐2 (TRAF3IP2) intermediate. Activation of AP‐1 and NF‐κB downstream of these interleukins induces MMP activity, increasing cardiac fibroblast migration. It is likely that additional pathways identified in noncardiac fibroblasts are also involved in cardiac fibroblast migration, however they remain to be characterized.


Figure 5. Akt‐mediated regulation of cardiac fibroblast proliferation. Growth factors such as PDGF and FGF bind to their cognate receptors, resulting in associated receptor tyrosine kinase (RTK) activation. Upon ligand binding, PI3K subunits p85 and p110 are recruited to the receptor to form the activated PI3K enzyme, catalyzing the conversion of PIP2 to PIP3. PIP3 recruits Akt to the plasma membrane, where it is phosphorylated by PDK1 thereby promoting its translocation into the nucleus. p70S6 Kinase is activated downstream of phospho‐Akt and in turn phosphorylates the S6 protein within the 40S ribosomal subunit, positively regulating cell growth and proliferation. Phospho‐Akt further promotes cell proliferation by phosphorylating and thereby deactivating GSK3. GSK3 flags Cyclin D1 for translocation into the cytoplasm of the cell, make it unavailable to regulate the cell cycle and resulting in cell‐cycle arrest.


Figure 6. Myofibroblast contractile response. Contraction of stress fibers occurs via calcium‐dependent and ‐independent signaling pathways in cardiac fibroblasts. Calcium‐dependent contraction is typically rapid and occurs primarily in peripheral stress fibers. Through receptors such as transient receptor potential cation (TRPC) channels, calcium‐dependent contraction occurs in response to an influx of Ca2+ ions, which form a complex with and activate calmodulin, resulting in myosin light chain kinase (MLCK) activation and subsequent phosphorylation of myosin light chain (MLC) bound to stress fibers. However, contraction is not sustained due to the activity of myosin phosphatase (MP) within the cell, which dephosphorylates and inactivates actin‐bound MLC. Conversely, calcium‐independent contraction is relatively slow and acts primarily on central stress fibers in sustained contractile events, usually in response to mechanical strain. Calcium‐independent contraction occurs primarily through integrin activation and downstream RhoA‐Rho‐GTPase‐associated kinase (ROCK) signaling, which inhibits MP to maintain phosphorylation of MLC, allowing for prolonged contractile events.
References
 1. Abe R , Donnelly SC , Peng T , Bucala R , Metz CN . Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites. J Immunol 166: 7556‐7562, 2001.
 2. Acharya A , Baek ST , Huang G , Eskiocak B , Goetsch S , Sung CY , Banfi S , Sauer MF , Olsen GS , Duffield JS , Olson EN , Tallquist MD . The bHLH transcription factor Tcf21 is required for lineage‐specific EMT of cardiac fibroblast progenitors. Development 139: 2139‐2149, 2012.
 3. Adapala RK , Thoppil RJ , Luther DJ , Paruchuri S , Meszaros JG , Chilian WM , Thodeti CK . TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J Mol Cell Cardiol 54: 45‐52, 2013.
 4. Agapitov AV , Haynes WG . Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 3: 1‐15, 2002.
 5. Alessi DR , James SR , Downes CP , Holmes AB , Gaffney PR , Reese CB , Cohen P . Characterization of a 3‐phosphoinositide‐dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7: 261‐269, 1997.
 6. Alexandrova AY , Arnold K , Schaub S , Vasiliev JM , Meister JJ , Bershadsky AD , Verkhovsky AB . Comparative dynamics of retrograde actin flow and focal adhesions: Formation of nascent adhesions triggers transition from fast to slow flow. PloS One 3: e3234, 2008.
 7. Amano M , Chihara K , Kimura K , Fukata Y , Nakamura N , Matsuura Y , Kaibuchi K . Formation of actin stress fibers and focal adhesions enhanced by Rho‐kinase. Science 275: 1308‐1311, 1997.
 8. Amano M , Ito M , Kimura K , Fukata Y , Chihara K , Nakano T , Matsuura Y , Kaibuchi K . Phosphorylation and activation of myosin by Rho‐associated kinase (Rho‐kinase). J Biol Chem 271: 20246‐20249, 1996.
 9. Amano M , Mukai H , Ono Y , Chihara K , Matsui T , Hamajima Y , Okawa K , Iwamatsu A , Kaibuchi K . Identification of a putative target for Rho as the serine‐threonine kinase protein kinase N. Science 271: 648‐650, 1996.
 10. Anderson TW , Vaughan AN , Cramer LP . Retrograde flow and myosin II activity within the leading cell edge deliver F‐actin to the lamella to seed the formation of graded polarity actomyosin II filament bundles in migrating fibroblasts. Mol Biol Cell 19: 5006‐5018, 2008.
 11. Annes JP , Munger JS , Rifkin DB . Making sense of latent TGFbeta activation. J Cell Sci 116: 217‐224, 2003.
 12. Anthis NJ , Haling JR , Oxley CL , Memo M , Wegener KL , Lim CJ , Ginsberg MH , Campbell ID . Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin‐induced integrin activation. J Biol Chem 284: 36700‐36710, 2009.
 13. Anthis NJ , Wegener KL , Ye F , Kim C , Goult BT , Lowe ED , Vakonakis I , Bate N , Critchley DR , Ginsberg MH , Campbell ID . The structure of an integrin/talin complex reveals the basis of inside‐out signal transduction. EMBO J 28: 3623‐3632, 2009.
 14. Arber S , Barbayannis FA , Hanser H , Schneider C , Stanyon CA , Bernard O , Caroni P . Regulation of actin dynamics through phosphorylation of cofilin by LIM‐kinase. Nature 393: 805‐809, 1998.
 15. Arnaout MA , Goodman SL , Xiong JP . Structure and mechanics of integrin‐based cell adhesion. Curr Opin Cell Biol 19: 495‐507, 2007.
 16. Arslan F , Smeets MB , Riem Vis PW , Karper JC , Quax PH , Bongartz LG , Peters JH , Hoefer IE , Doevendans PA , Pasterkamp G , de Kleijn DP . Lack of fibronectin‐EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction. Circ Res 108: 582‐592, 2011.
 17. Arthur WT , Burridge K . RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol Biol Cell 12: 2711‐2720, 2001.
 18. Arthur WT , Petch LA , Burridge K . Integrin engagement suppresses RhoA activity via a c‐Src‐dependent mechanism. Curr Biol 10: 719‐722, 2000.
 19. Asparuhova MB , Ferralli J , Chiquet M , Chiquet‐Ehrismann R . The transcriptional regulator megakaryoblastic leukemia‐1 mediates serum response factor‐independent activation of tenascin‐C transcription by mechanical stress. FASEB J 25: 3477‐3488, 2011.
 20. Asparuhova MB , Gelman L , Chiquet M . Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress. Scand J Med Sci Sports 19: 490‐499, 2009.
 21. Assoian RK , Fleurdelys BE , Stevenson HC , Miller PJ , Madtes DK , Raines EW , Ross R , Sporn MB . Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A 84: 6020‐6024, 1987.
 22. 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.
 23. Bakin AV , Safina A , Rinehart C , Daroqui C , Darbary H , Helfman DM . A critical role of tropomyosins in TGF‐beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 15: 4682‐4694, 2004.
 24. Bakolitsa C , Cohen DM , Bankston LA , Bobkov AA , Cadwell GW , Jennings L , Critchley DR , Craig SW , Liddington RC . Structural basis for vinculin activation at sites of cell adhesion. Nature 430: 583‐586, 2004.
 25. Bamburg JR , McGough A , Ono S . Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol 9: 364‐370, 1999.
 26. Barbolina MV , Stack MS . Membrane type 1‐matrix metalloproteinase: Substrate diversity in pericellular proteolysis. Sem Cell Dev Biol 19: 24‐33, 2008.
 27. Bashey RI , Martinez‐Hernandez A , Jimenez SA . Isolation, characterization, and localization of cardiac collagen type VI. Associations with other extracellular matrix components. Circ Res 70: 1006‐1017, 1992.
 28. Bauer EA , Silverman N , Busiek DF , Kronberger A , Deuel TF . Diminished response of Werner's syndrome fibroblasts to growth factors PDGF and FGF. Science 234: 1240‐1243, 1986.
 29. Bauersachs J , Thum T . Biogenesis and regulation of cardiovascular microRNAs. Circ Res 109: 334‐347, 2011.
 30. Bellin RM , Kubicek JD , Frigault MJ , Kamien AJ , Steward RL, Jr. , Barnes HM , Digiacomo MB , Duncan LJ , Edgerly CK , Morse EM , Park CY , Fredberg JJ , Cheng CM , LeDuc PR . Defining the role of syndecan‐4 in mechanotransduction using surface‐modification approaches. Proc Natl Acad Sci U S A 106: 22102‐22107, 2009.
 31. Berge G , Maelandsmo GM . Evaluation of potential interactions between the metastasis‐associated protein S100A4 and the tumor suppressor protein p53. Amino Acids 41: 863‐873, 2011.
 32. Bergman MR , Cheng S , Honbo N , Piacentini L , Karliner JS , Lovett DH . A functional activating protein 1 (AP‐1) site regulates matrix metalloproteinase 2 (MMP‐2) transcription by cardiac cells through interactions with JunB‐Fra1 and JunB‐FosB heterodimers. Biochem J 369: 485‐496, 2003.
 33. Bernanke DH , Markwald RR . Effects of hyaluronic acid on cardiac cushion tissue cells in collagen matrix cultures. Tex Rep Biol Med 39: 271‐285, 1979.
 34. Berry MF , Engler AJ , Woo YJ , Pirolli TJ , Bish LT , Jayasankar V , Morine KJ , Gardner TJ , Discher DE , Sweeney HL . Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am J Physiol Heart Circ Physiol 290: H2196‐2203, 2006.
 35. Bhana B , Iyer RK , Chen WL , 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.
 36. Bing OH , Ngo HQ , Humphries DE , Robinson KG , Lucey EC , Carver W , Brooks WW , Conrad CH , Hayes JA , Goldstein RH . Localization of alpha1(I) collagen mRNA in myocardium from the spontaneously hypertensive rat during the transition from compensated hypertrophy to failure. J Mol Cell Cardiol 29: 2335‐2344, 1997.
 37. Bishop JE , Laurent GJ . Collagen turnover and its regulation in the normal and hypertrophying heart. Eur Heart J 16(Suppl C): 38‐44, 1995.
 38. Blomer N , Pachel C , Hofmann U , Nordbeck P , Bauer W , Mathes D , Frey A , Bayer B , Vogel B , Ertl G , Bauersachs J , Frantz S . 5‐Lipoxygenase facilitates healing after myocardial infarction. Basic Res Cardiol 108: 367, 2013.
 39. Blumer KJ , Johnson GL . Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci 19: 236‐240, 1994.
 40. Boettner B , Van Aelst L . Control of cell adhesion dynamics by Rap1 signaling. Curr Opin Cell Biol 21: 684‐693, 2009.
 41. Booz GW , Baker KM . Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. Cardiovasc Res 30: 537‐543, 1995.
 42. Borg TK , Rubin K , Lundgren E , Borg K , Obrink B . Recognition of extracellular matrix components by neonatal and adult cardiac myocytes. Dev Biol 104: 86‐96, 1984.
 43. Bos JL . Linking Rap to cell adhesion. Curr Opin Cell Biol 17: 123‐128, 2005.
 44. Bos JL , Rehmann H , Wittinghofer A . GEFs and GAPs: Critical elements in the control of small G proteins. Cell 129: 865‐877, 2007.
 45. Bosman FT , Stamenkovic I . Functional structure and composition of the extracellular matrix. The Journal of pathology 200: 423‐428, 2003.
 46. Bouaouina M , Lad Y , Calderwood DA . The N‐terminal domains of talin cooperate with the phosphotyrosine binding‐like domain to activate beta1 and beta3 integrins. J Biol Chem 283: 6118‐6125, 2008.
 47. Boutahar N , Guignandon A , Vico L , Lafage‐Proust MH . Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline‐rich tyrosine kinase 2 tyrosine sites involved in ERK activation. J Biol Chem 279: 30588‐30599, 2004.
 48. Brilla CG , Weber KT . Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 26: 671‐677, 1992.
 49. Brilla CG , Zhou G , Matsubara L , Weber KT . Collagen metabolism in cultured adult rat cardiac fibroblasts: Response to angiotensin II and aldosterone. J Mol Cell Cardiol 26: 809‐820, 1994.
 50. Brodersen P , Voinnet O . Revisiting the principles of microRNA target recognition and mode of action. Nature Rev Mol Cell Biol 10: 141‐148, 2009.
 51. Brooks WW , Healey NA , Sen S , Conrad CH , Bing OH . Oxygen cost of stress development in hypertrophied and failing hearts from the spontaneously hypertensive rat. Hypertension 21: 56‐64, 1993.
 52. Brown MC , Perrotta JA , Turner CE . Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding. J Cell Biol 135: 1109‐1123, 1996.
 53. Brown MC , West KA , Turner CE . Paxillin‐dependent paxillin kinase linker and p21‐activated kinase localization to focal adhesions involves a multistep activation pathway. Mol Biol Cell 13: 1550‐1565, 2002.
 54. Brown RD , Jones GM , Laird RE , Hudson P , Long CS . Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts. Biochem Bioph Res Co 362: 200‐205, 2007.
 55. Bryce NS , Schevzov G , Ferguson V , Percival JM , Lin JJ , Matsumura F , Bamburg JR , Jeffrey PL , Hardeman EC , Gunning P , Weinberger RP . Specification of actin filament function and molecular composition by tropomyosin isoforms. Mol Biol Cell 14: 1002‐1016, 2003.
 56. Buja LM . Modulation of the myocardial response to ischemia. Lab Invest 78: 1345‐1373, 1998.
 57. Bujak M , Frangogiannis NG . The role of TGF‐beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74: 184‐195, 2007.
 58. Burgering BM , Coffer PJ . Protein kinase B (c‐Akt) in phosphatidylinositol‐3‐OH kinase signal transduction. Nature 376: 599‐602, 1995.
 59. Burgess ML , Terracio L , Hirozane T , Borg TK . Differential integrin expression by cardiac fibroblasts from hypertensive and exercise‐trained rat hearts. Cardiovasc Pathol 11: 78‐87, 2002.
 60. Burridge K . Are stress fibres contractile? Nature 294: 691‐692, 1981.
 61. Burridge K , Chrzanowska‐Wodnicka M , Zhong C . Focal adhesion assembly. Trends Cell Biol 7: 342‐347, 1997.
 62. Burridge K , Wennerberg K . Rho and Rac take center stage. Cell 116: 167‐179, 2004.
 63. Burridge K , Wittchen ES . The tension mounts: Stress fibers as force‐generating mechanotransducers. J Cell Biol 200: 9‐19, 2013.
 64. Burstein B , Libby E , Calderone A , Nattel S . Differential behaviors of atrial versus ventricular fibroblasts: A potential role for platelet‐derived growth factor in atrial‐ventricular remodeling differences. Circulation 117: 1630‐1641, 2008.
 65. Bustos RI , Forget MA , Settleman JE , Hansen SH . Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr Biol 18: 1606‐1611, 2008.
 66. Butt RP , Laurent GJ , Bishop JE . Collagen production and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors. Eur J Cell Biol 68: 330‐335, 1995.
 67. Cai Y , Biais N , Giannone G , Tanase M , Jiang G , Hofman JM , Wiggins CH , Silberzan P , Buguin A , Ladoux B , Sheetz MP . Nonmuscle myosin IIA‐dependent force inhibits cell spreading and drives F‐actin flow. Biophys J 91: 3907‐3920, 2006.
 68. Calderwood DA . Talin controls integrin activation. Biochem Soc Tran 32: 434‐437, 2004.
 69. Calderwood DA , Fujioka Y , de Pereda JM , Garcia‐Alvarez B , Nakamoto T , Margolis B , McGlade CJ , Liddington RC , Ginsberg MH . Integrin beta cytoplasmic domain interactions with phosphotyrosine‐binding domains: A structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A 100: 2272‐2277, 2003.
 70. Calderwood DA , Yan B , de Pereda JM , Alvarez BG , Fujioka Y , Liddington RC , Ginsberg MH . The phosphotyrosine binding‐like domain of talin activates integrins. J Biol Chem 277: 21749‐21758, 2002.
 71. Calderwood DA , Zent R , Grant R , Rees DJ , Hynes RO , Ginsberg MH . The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem 274: 28071‐28074, 1999.
 72. Camelliti P , Green CR , LeGrice I , Kohl P . Fibroblast network in rabbit sinoatrial node: Structural and functional identification of homogeneous and heterogeneous cell coupling. Circ Res 94: 828‐835, 2004.
 73. Camenisch TD , Spicer AP , Brehm‐Gibson T , Biesterfeldt J , Augustine ML , Calabro A, Jr. , Kubalak S , Klewer SE , McDonald JA . Disruption of hyaluronan synthase‐2 abrogates normal cardiac morphogenesis and hyaluronan‐mediated transformation of epithelium to mesenchyme. J Clin Invest 106: 349‐360, 2000.
 74. Campbell SE , Katwa LC . Angiotensin II stimulated expression of transforming growth factor‐beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 29: 1947‐1958, 1997.
 75. Campisi J . The biology of replicative senescence. Eur J Cancer 33: 703‐709, 1997.
 76. Carey DJ . Syndecans: Multifunctional cell‐surface co‐receptors. Biochem J 327 (Pt 1): 1‐16, 1997.
 77. Carisey A , Tsang R , Greiner AM , Nijenhuis N , Heath N , Nazgiewicz A , Kemkemer R , Derby B , Spatz J , Ballestrem C . Vinculin regulates the recruitment and release of core focal adhesion proteins in a force‐dependent manner. Curr Biol 23: 271‐281, 2013.
 78. Cary LA , Klinghoffer RA , Sachsenmaier C , Cooper JA . SRC catalytic but not scaffolding function is needed for integrin‐regulated tyrosine phosphorylation, cell migration, and cell spreading. Mol Cell Biol 22: 2427‐2440, 2002.
 79. Chan MW , Arora PD , Bozavikov P , McCulloch CA . FAK, PIP5KIgamma and gelsolin cooperatively mediate force‐induced expression of alpha‐smooth muscle actin. J Cell Sci 122: 2769‐2781, 2009.
 80. Chan MW , Chaudary F , Lee W , Copeland JW , McCulloch CA . Force‐induced myofibroblast differentiation through collagen receptors is dependent on mammalian diaphanous (mDia). J Biol Chem 285: 9273‐9281, 2010.
 81. Chang F , Lemmon CA , Park D , Romer LH . FAK potentiates Rac1 activation and localization to matrix adhesion sites: A role for betaPIX. Mol Biol Cell 18: 253‐264, 2007.
 82. 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.
 83. Chen CS . Mechanotransduction ‐ a field pulling together? J Cell Sci 121: 3285‐3292, 2008.
 84. Chen HC , Appeddu PA , Parsons JT , Hildebrand JD , Schaller MD , Guan JL . Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem 270: 16995‐16999, 1995.
 85. Chen K , Li D , Zhang X , Hermonat PL , Mehta JL . Anoxia‐reoxygenation stimulates collagen type‐I and MMP‐1 expression in cardiac fibroblasts: Modulation by the PPAR‐gamma ligand pioglitazone. J Cardiovasc Pharm 44: 682‐687, 2004.
 86. Chen L , Wu Q , Guo F , Xia B , Zuo J . Expression of Dishevelled‐1 in wound healing after acute myocardial infarction: Possible involvement in myofibroblast proliferation and migration. J Cell Mol Med 8: 257‐264, 2004.
 87. Chen M , Masaki T , Sawamura T . LOX‐1, the receptor for oxidized low‐density lipoprotein identified from endothelial cells: Implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther 95: 89‐100, 2002.
 88. Chen SJ , Yuan W , Lo S , Trojanowska M , Varga J . Interaction of smad3 with a proximal smad‐binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF‐beta. J Cell Physiol 183: 381‐392, 2000.
 89. Chen W , Saxena A , Li N , Sun J , Gupta A , Lee DW , Tian Q , Dobaczewski M , Frangogiannis NG . Endogenous IRAK‐M attenuates postinfarction remodeling through effects on macrophages and fibroblasts. Arterioscl Throm Vas biol 32: 2598‐2608, 2012.
 90. Chen Y , Banda M , Speyer CL , Smith JS , Rabson AB , Gorski DH . Regulation of the expression and activity of the antiangiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA‐221. Mol Cell Biol 30: 3902‐3913, 2010.
 91. Chen Y , Shi‐Wen X , van Beek J , Kennedy L , McLeod M , Renzoni EA , Bou‐Gharios G , Wilcox‐Adelman S , Goetinck PF , Eastwood M , Black CM , Abraham DJ , Leask A . Matrix contraction by dermal fibroblasts requires transforming growth factor‐beta/activin‐linked kinase 5, heparan sulfate‐containing proteoglycans, and MEK/ERK: Insights into pathological scarring in chronic fibrotic disease. Am J Pathol 167: 1699‐1711, 2005.
 92. Chen YG , Liu F , Massague J . Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J 16: 3866‐3876, 1997.
 93. Cheng TH , Cheng PY , Shih NL , Chen IB , Wang DL , Chen JJ . Involvement of reactive oxygen species in angiotensin II‐induced endothelin‐1 gene expression in rat cardiac fibroblasts. J Am Coll Cardiol 42: 1845‐1854, 2003.
 94. Cheng Y , Liu X , Yang J , Lin Y , Xu DZ , Lu Q , Deitch EA , Huo Y , Delphin ES , Zhang C . MicroRNA‐145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 105: 158‐166, 2009.
 95. Chikumi H , Fukuhara S , Gutkind JS . Regulation of G protein‐linked guanine nucleotide exchange factors for Rho, PDZ‐RhoGEF, and LARG by tyrosine phosphorylation: Evidence of a role for focal adhesion kinase. J Biol Chem 277: 12463‐12473, 2002.
 96. Chiloeches A , Paterson HF , Marais R , Clerk A , Marshall CJ , Sugden PH . Regulation of Ras.GTP loading and Ras‐Raf association in neonatal rat ventricular myocytes by G protein‐coupled receptor agonists and phorbol ester. Activation of the extracellular signal‐regulated kinase cascade by phorbol ester is mediated by Ras. J Biol Chem 274: 19762‐19770, 1999.
 97. Chiquet M , Gelman L , Lutz R , Maier S . From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim Biophys Acta 1793: 911‐920, 2009.
 98. Chohan PK , Singh RB , Dhalla NS , Netticadan T . L‐arginine administration recovers sarcoplasmic reticulum function in ischemic reperfused hearts by preventing calpain activation. Cardiovasc Res 69: 152‐163, 2006.
 99. Choi CK , Vicente‐Manzanares M , Zareno J , Whitmore LA , Mogilner A , Horwitz AR . Actin and alpha‐actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor‐independent manner. Nat Cell Biol 10: 1039‐1050, 2008.
 100. Christia P , Bujak M , Gonzalez‐Quesada C , Chen W , Dobaczewski M , Reddy A , Frangogiannis NG . Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction. J Histochem Cytochem 61: 555‐570, 2013.
 101. Chu W , Li X , Li C , Wan L , Shi H , Song X , Liu X , Chen X , Zhang C , Shan H , Lu Y , Yang B . TGFBR3, a potential negative regulator of TGF‐beta signaling, protects cardiac fibroblasts from hypoxia‐induced apoptosis. J Cell Physiol 226: 2586‐2594, 2011.
 102. Chua CC , Hamdy RC , Chua BH . Angiotensin II induces TIMP‐1 production in rat heart endothelial cells. Biochim Biophys Acta 1311: 175‐180, 1996.
 103. Cicoira M , Rossi A , Bonapace S , Zanolla L , Golia G , Franceschini L , Caruso B , Marino PN , Zardini P . Independent and additional prognostic value of aminoterminal propeptide of type III procollagen circulating levels in patients with chronic heart failure. J Card Fail 10: 403‐411, 2004.
 104. 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.
 105. Cleutjens JP , Verluyten MJ , Smiths JF , Daemen MJ . Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 147: 325‐338, 1995.
 106. Colige A , Vandenberghe I , Thiry M , Lambert CA , Van Beeumen J , Li SW , Prockop DJ , Lapiere CM , Nusgens BV . Cloning and characterization of ADAMTS‐14, a novel ADAMTS displaying high homology with ADAMTS‐2 and ADAMTS‐3. J Biol Chem 277: 5756‐5766, 2002.
 107. Colombelli J , Besser A , Kress H , Reynaud EG , Girard P , Caussinus E , Haselmann U , Small JV , Schwarz US , Stelzer EH . Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J Cell Sci 122: 1665‐1679, 2009.
 108. Conrad CH , Brooks WW , Hayes JA , Sen S , Robinson KG , Bing OH . Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 91: 161‐170, 1995.
 109. Cook TA , Nagasaki T , Gundersen GG . Rho guanosine triphosphatase mediates the selective stabilization of microtubules induced by lysophosphatidic acid. J Cell Biol 141: 175‐185, 1998.
 110. Corda S , Samuel JL , Rappaport L . Extracellular matrix and growth factors during heart growth. Heart Fail Rev 5: 119‐130, 2000.
 111. Cortez DM , Feldman MD , Mummidi S , Valente AJ , Steffensen B , Vincenti M , Barnes JL , Chandrasekar B . IL‐17 stimulates MMP‐1 expression in primary human cardiac fibroblasts via p38 MAPK‐ and ERK1/2‐dependent C/EBP‐beta, NF‐ukappaB, and AP‐1 activation. Am J Physiol Heart Circ Physiol 293: H3356‐3365, 2007.
 112. Crabos M , Roth M , Hahn AW , Erne P . Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts. Coupling to signaling systems and gene expression. J Clin Invest 93: 2372‐2378, 1994.
 113. Cramer LP . Mechanism of cell rear retraction in migrating cells. Curr Opin Cell Biol 25: 591‐599, 2013.
 114. 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.
 115. 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 Ph 300: C176‐186, 2011.
 116. Czubryt MP . Common threads in cardiac fibrosis, infarct scar formation, and wound healing. Fibrogen Tissue Rep 5: 19, 2012.
 117. D'Addario M , Arora PD , Ellen RP , McCulloch CA . Interaction of p38 and Sp1 in a mechanical force‐induced, beta 1 integrin‐mediated transcriptional circuit that regulates the actin‐binding protein filamin‐A. J Biol Chem 277: 47541‐47550, 2002.
 118. D'Angelo M , Billings PC , Pacifici M , Leboy PS , Kirsch T . Authentic matrix vesicles contain active metalloproteases (MMP). a role for matrix vesicle‐associated MMP‐13 in activation of transforming growth factor‐beta. J Biol Chem 276: 11347‐11353, 2001.
 119. Dadson K , Chasiotis H , Wannaiampikul S , Tungtrongchitr R , Xu A , Sweeney G . Adiponectin mediated APPL1‐AMPK signaling induces cell migration, MMP activation, and collagen remodeling in cardiac fibroblasts. J Cell Biochem 115: 785‐793, 2014.
 120. Dang I , Gorelik R , Sousa‐Blin C , Derivery E , Guerin C , Linkner J , Nemethova M , Dumortier JG , Giger FA , Chipysheva TA , Ermilova VD , Vacher S , Campanacci V , Herrada I , Planson AG , Fetics S , Henriot V , David V , Oguievetskaia K , Lakisic G , Pierre F , Steffen A , Boyreau A , Peyrieras N , Rottner K , Zinn‐Justin S , Cherfils J , Bieche I , Alexandrova AY , David NB , Small JV , Faix J , Blanchoin L , Gautreau A . Inhibitory signalling to the Arp2/3 complex steers cell migration. Nature 503: 281‐284, 2013.
 121. 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.
 122. Davis J , Burr AR , Davis GF , Birnbaumer L , Molkentin JD . A TRPC6‐dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell 23: 705‐715, 2012.
 123. Davis J , Molkentin JD . Myofibroblasts: Trust your heart and let fate decide. J Mol Cell Cardiol 70: 9‐18, 2014.
 124. de Souza RR . Aging of myocardial collagen. Biogerontology 3: 325‐335, 2002.
 125. Defilippi P , Di Stefano P , Cabodi S . p130Cas: A versatile scaffold in signaling networks. Trends Cell Biol 16: 257‐263, 2006.
 126. del Pozo MA , Alderson NB , Kiosses WB , Chiang HH , Anderson RG , Schwartz MA . Integrins regulate Rac targeting by internalization of membrane domains. Science 303: 839‐842, 2004.
 127. Delmas C , Manenti S , Boudjelal A , Peyssonnaux C , Eychene A , Darbon JM . The p42/p44 mitogen‐activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells. J Biol Chem 276: 34958‐34965, 2001.
 128. DeMali KA , Wennerberg K , Burridge K . Integrin signaling to the actin cytoskeleton. Curr Opin Cell Biol 15: 572‐582, 2003.
 129. Denhez F , Wilcox‐Adelman SA , Baciu PC , Saoncella S , Lee S , French B , Neveu W , Goetinck PF . Syndesmos, a syndecan‐4 cytoplasmic domain interactor, binds to the focal adhesion adaptor proteins paxillin and Hic‐5. J Biol Chem 277: 12270‐12274, 2002.
 130. Deschamps AM , Spinale FG . Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation. Cardiovasc Res 69: 666‐676, 2006.
 131. Desmouliere A , Gabbiani G . Modulation of fibroblastic cytoskeletal features during pathological situations: The role of extracellular matrix and cytokines. Cell Motil Cytoskeleton 29: 195‐203, 1994.
 132. 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.
 133. Diehl JA , Cheng M , Roussel MF , Sherr CJ . Glycogen synthase kinase‐3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12: 3499‐3511, 1998.
 134. Diez C , Nestler M , Friedrich U , Vieth M , Stolte M , Hu K , Hoppe J , Simm A . Down‐regulation of Akt/PKB in senescent cardiac fibroblasts impairs PDGF‐induced cell proliferation. Cardiovasc Res 49: 731‐740, 2001.
 135. Dinh DT , Frauman AG , Johnston CI , Fabiani ME . Angiotensin receptors: Distribution, signalling and function. Clin Sci (Lond) 100: 481‐492, 2001.
 136. Dixon IM , Hao J , Reid NL , Roth JC . Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters. Cardiovasc Res 46: 286‐297, 2000.
 137. Dobaczewski M , Bujak M , Li N , Gonzalez‐Quesada C , Mendoza LH , Wang XF , Frangogiannis NG . Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ Res 107: 418‐428, 2010.
 138. Dong S , Ma W , Hao B , Hu F , Yan L , Yan X , Wang Y , Chen Z , Wang Z . microRNA‐21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up‐regulating Bcl‐2. Int J Clin Exp Pathol 7: 565‐574, 2014.
 139. Driesen RB , Nagaraju CK , Abi‐Char J , Coenen T , Lijnen PJ , Fagard RH , Sipido KR , Petrov VV . Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc Res 101: 411‐422, 2014.
 140. Du J , Xie J , Zhang Z , Tsujikawa H , Fusco D , Silverman D , Liang B , Yue L . TRPM7‐mediated Ca2 +signals confer fibrogenesis in human atrial fibrillation. Circ Res 106: 992‐1003, 2010.
 141. Dubash AD , Wennerberg K , Garcia‐Mata R , Menold MM , Arthur WT , Burridge K . A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J Cell Sci 120: 3989‐3998, 2007.
 142. Dubey RK , Gillespie DG , Mi Z , Jackson EK . Cardiac fibroblasts express the cAMP‐adenosine pathway. Hypertension 36: 337‐342, 2000.
 143. Dubey RK , Gillespie DG , Mi Z , Jackson EK . Exogenous and endogenous adenosine inhibits fetal calf serum‐induced growth of rat cardiac fibroblasts: Role of A2B receptors. Circulation 96: 2656‐2666, 1997.
 144. Dubey RK , Gillespie DG , Osaka K , Suzuki F , Jackson EK . Adenosine inhibits growth of rat aortic smooth muscle cells. Possible role of A2b receptor. Hypertension 27: 786‐793, 1996.
 145. 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.
 146. Dumbauld DW , Lee TT , Singh A , Scrimgeour J , Gersbach CA , Zamir EA , Fu J , Chen CS , Curtis JE , Craig SW , Garcia AJ . How vinculin regulates force transmission. Proc Natl Acad Sci U S A 110: 9788‐9793, 2013.
 147. Dunlevy JR , Couchman JR . Interleukin‐8 induces motile behavior and loss of focal adhesions in primary fibroblasts. J Cell Sci 108(Pt 1): 311‐321, 1995.
 148. Eghbali M . Cardiac fibroblasts: Function, regulation of gene expression, and phenotypic modulation. Basic Res Cardiol 87(Suppl 2): 183‐189, 1992.
 149. Eghbali M , Weber KT . Collagen and the myocardium: Fibrillar structure, biosynthesis and degradation in relation to hypertrophy and its regression. Mol Cell Biochem 96: 1‐14, 1990.
 150. Eimer W , Niermann M , Eppe MA , Jockusch BM . Molecular shape of vinculin in aqueous solution. J Mol Biol 229: 146‐152, 1993.
 151. Ekholm SV , Reed SI . Regulation of G(1) cyclin‐dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 12: 676‐684, 2000.
 152. Elledge SJ . Cell cycle checkpoints: Preventing an identity crisis. Science 274: 1664‐1672, 1996.
 153. Ellerbroek SM , Wennerberg K , Burridge K . Serine phosphorylation negatively regulates RhoA in vivo. J Biol Chem 278: 19023‐19031, 2003.
 154. Ellis IR , Jones SJ , Lindsay Y , Ohe G , Schor AM , Schor SL , Leslie NR . Migration Stimulating Factor (MSF) promotes fibroblast migration by inhibiting AKT. Cell Signal 22: 1655‐1659, 2010.
 155. Esparza‐Lopez J , Montiel JL , Vilchis‐Landeros MM , Okadome T , Miyazono K , Lopez‐Casillas F . Ligand binding and functional properties of betaglycan, a co‐receptor of the transforming growth factor‐beta superfamily. Specialized binding regions for transforming growth factor‐beta and inhibin A. J Biol Chem 276: 14588‐14596, 2001.
 156. 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.
 157. 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.
 158. Felsenfeld DP , Schwartzberg PL , Venegas A , Tse R , Sheetz MP . Selective regulation of integrin–cytoskeleton interactions by the tyrosine kinase Src. Nat Cell Biol 1: 200‐206, 1999.
 159. Feng J , Ito M , Ichikawa K , Isaka N , Nishikawa M , Hartshorne DJ , Nakano T . Inhibitory phosphorylation site for Rho‐associated kinase on smooth muscle myosin phosphatase. J Biol Chem 274: 37385‐37390, 1999.
 160. Fisher SA , Absher M . Norepinephrine and ANG II stimulate secretion of TGF‐beta by neonatal rat cardiac fibroblasts in vitro. Am J Physiol 268: C910‐917, 1995.
 161. Fitzgerald KA , Bowie AG , Skeffington BS , O'Neill LA . Ras, protein kinase C zeta, and I kappa B kinases 1 and 2 are downstream effectors of CD44 during the activation of NF‐kappa B by hyaluronic acid fragments in T‐24 carcinoma cells. J Immunol 164: 2053‐2063, 2000.
 162. Fonseca PM , Shin NY , Brabek J , Ryzhova L , Wu J , Hanks SK . Regulation and localization of CAS substrate domain tyrosine phosphorylation. Cell Signal 16: 621‐629, 2004.
 163. Frangogiannis NG . Matricellular proteins in cardiac adaptation and disease. Physiol Rev 92: 635‐688, 2012.
 164. Frangogiannis NG . The mechanistic basis of infarct healing. Antioxid Redox Signal 8: 1907‐1939, 2006.
 165. Frangogiannis NG . Regulation of the inflammatory response in cardiac repair. Circ Res 110: 159‐173, 2012.
 166. Frangogiannis NG , Michael LH , Entman ML . Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb). Cardiovasc Res 48: 89‐100, 2000.
 167. Freed DH , Chilton L , Li Y , Dangerfield AL , Raizman JE , Rattan SG , Visen N , Hryshko LV , Dixon IM . Role of myosin light chain kinase in cardiotrophin‐1‐induced cardiac myofibroblast cell migration. Am J Physiol Heart Circ Physiol 301: H514‐522, 2011.
 168. Freed DH , Moon MC , Borowiec AM , Jones SC , Zahradka P , Dixon IM . Cardiotrophin‐1: Expression in experimental myocardial infarction and potential role in post‐MI wound healing. Mol Cell Biochem 254: 247‐256, 2003.
 169. Frey RS , Mulder KM . Involvement of extracellular signal‐regulated kinase 2 and stress‐activated protein kinase/Jun N‐terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res 57: 628‐633, 1997.
 170. Frey RS , Mulder KM . TGFbeta regulation of mitogen‐activated protein kinases in human breast cancer cells. Cancer Lett 117: 41‐50, 1997.
 171. Fujishiro SH , Tanimura S , Mure S , Kashimoto Y , Watanabe K , Kohno M . ERK1/2 phosphorylate GEF‐H1 to enhance its guanine nucleotide exchange activity toward RhoA. Biochem Bioph Res Co 368: 162‐167, 2008.
 172. Fukata M , Nakagawa M , Kaibuchi K . Roles of Rho‐family GTPases in cell polarisation and directional migration. Curr Opin Cell Biol 15: 590‐597, 2003.
 173. Gabbiani G , Hirschel BJ , Ryan GB , Statkov PR , Majno G . Granulation tissue as a contractile organ. A study of structure and function. J Exp Med 135: 719‐734, 1972.
 174. Ganz A , Lambert M , Saez A , Silberzan P , Buguin A , Mege RM , Ladoux B . Traction forces exerted through N‐cadherin contacts. Biol Cell 98: 721‐730, 2006.
 175. Gao X , He X , Luo B , Peng L , Lin J , Zuo Z . Angiotensin II increases collagen I expression via transforming growth factor‐beta1 and extracellular signal‐regulated kinase in cardiac fibroblasts. Eur J Pharmacol 606: 115‐120, 2009.
 176. Geiger B , Bershadsky A . Assembly and mechanosensory function of focal contacts. Curr Opin Cell Biol 13: 584‐592, 2001.
 177. Geiger B , Bershadsky A , Pankov R , Yamada KM . Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nature Rev Mol Cell Biol 2: 793‐805, 2001.
 178. Geiger B , Spatz JP , Bershadsky AD . Environmental sensing through focal adhesions. Nature Rev Mol Cell Biol 10: 21‐33, 2009.
 179. Ginsberg MH , Wencel JD , White JG , Plow EF . Binding of fibronectin to alpha‐granule‐deficient platelets. J Cell Biol 97: 571‐573, 1983.
 180. Goffin JM , Pittet P , Csucs G , Lussi JW , Meister JJ , Hinz B . Focal adhesion size controls tension‐dependent recruitment of alpha‐smooth muscle actin to stress fibers. J Cell Biol 172: 259‐268, 2006.
 181. Gondokaryono SP , Ushio H , Niyonsaba F , Hara M , Takenaka H , Jayawardana ST , Ikeda S , Okumura K , Ogawa H . The extra domain A of fibronectin stimulates murine mast cells via toll‐like receptor 4. J Leukoc Biol 82: 657‐665, 2007.
 182. Grigorian M , Andresen S , Tulchinsky E , Kriajevska M , Carlberg C , Kruse C , Cohn M , Ambartsumian N , Christensen A , Selivanova G , Lukanidin E . Tumor suppressor p53 protein is a new target for the metastasis‐associated Mts1/S100A4 protein: Functional consequences of their interaction. J Biol Chem 276: 22699‐22708, 2001.
 183. Grinnell F . Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 124: 401‐404, 1994.
 184. Guilluy C , Garcia‐Mata R , Burridge K . Rho protein crosstalk: Another social network? Trends Cell Biol 21: 718‐726, 2011.
 185. Guilluy C , Swaminathan V , Garcia‐Mata R , O'Brien ET , Superfine R , Burridge K . The Rho GEFs LARG and GEF‐H1 regulate the mechanical response to force on integrins. Nat Cell Biol 13: 722‐727, 2011.
 186. Gunning P , O'Neill G , Hardeman E . Tropomyosin‐based regulation of the actin cytoskeleton in time and space. Physiol Rev 88: 1‐35, 2008.
 187. Gunning PW , Schevzov G , Kee AJ , Hardeman EC . Tropomyosin isoforms: Divining rods for actin cytoskeleton function. Trends Cell Biol 15: 333‐341, 2005.
 188. Guo WH , Wang YL . Retrograde fluxes of focal adhesion proteins in response to cell migration and mechanical signals. Mol Biol Cell 18: 4519‐4527, 2007.
 189. Guo XG , Uzui H , Mizuguchi T , Ueda T , Chen JZ , Lee JD . Imidaprilat inhibits matrix metalloproteinase‐2 activity in human cardiac fibroblasts induced by interleukin‐1beta via NO‐dependent pathway. Int J Cardiol 126: 414‐420, 2008.
 190. Gupton SL , Anderson KL , Kole TP , Fischer RS , Ponti A , Hitchcock‐DeGregori SE , Danuser G , Fowler VM , Wirtz D , Hanein D , Waterman‐Storer CM . Cell migration without a lamellipodium: Translation of actin dynamics into cell movement mediated by tropomyosin. J Cell Biol 168: 619‐631, 2005.
 191. Halliday NL , Tomasek JJ . Mechanical properties of the extracellular matrix influence fibronectin fibril assembly in vitro. Exp Cell Res 217: 109‐117, 1995.
 192. Han J , Lim CJ , Watanabe N , Soriani A , Ratnikov B , Calderwood DA , Puzon‐McLaughlin W , Lafuente EM , Boussiotis VA , Shattil SJ , Ginsberg MH . Reconstructing and deconstructing agonist‐induced activation of integrin alphaIIbbeta3. Curr Biol 16: 1796‐1806, 2006.
 193. Hanahan D , Weinberg RA . The hallmarks of cancer. Cell 100: 57‐70, 2000.
 194. Harada M , Luo X , Qi XY , Tadevosyan A , Maguy A , Ordog B , Ledoux J , Kato T , Naud P , Voigt N , Shi Y , Kamiya K , Murohara T , Kodama I , Tardif JC , Schotten U , Van Wagoner DR , Dobrev D , Nattel S . Transient receptor potential canonical‐3 channel‐dependent fibroblast regulation in atrial fibrillation. Circulation 126: 2051‐2064, 2012.
 195. Harris ES , Li F , Higgs HN . The mouse formin, FRLalpha, slows actin filament barbed end elongation, competes with capping protein, accelerates polymerization from monomers, and severs filaments. J Biol Chem 279: 20076‐20087, 2004.
 196. Hauck CR , Sieg DJ , Hsia DA , Loftus JC , Gaarde WA , Monia BP , Schlaepfer DD . Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor‐stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 61: 7079‐7090, 2001.
 197. Haudek SB , Cheng J , Du J , Wang Y , Hermosillo‐Rodriguez J , Trial J , Taffet GE , Entman ML . Monocytic fibroblast precursors mediate fibrosis in angiotensin‐II‐induced cardiac hypertrophy. J Mol Cell Cardiol 49: 499‐507, 2010.
 198. Hayakawa K , Tatsumi H , Sokabe M . Actin filaments function as a tension sensor by tension‐dependent binding of cofilin to the filament. J Cell Biol 195: 721‐727, 2011.
 199. He Y , Esser P , Schacht V , Bruckner‐Tuderman L , Has C . Role of kindlin‐2 in fibroblast functions: Implications for wound healing. J Invest Dermatol 131: 245‐256, 2011.
 200. Heath JP , Holifield BF . On the mechanisms of cortical actin flow and its role in cytoskeletal organisation of fibroblasts. Sym Soc Exp Biol 47: 35‐56, 1993.
 201. Heldin CH , Miyazono K , ten Dijke P . TGF‐beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465‐471, 1997.
 202. Helsten TL , Bunch TA , Kato H , Yamanouchi J , Choi SH , Jannuzi AL , Feral CC , Ginsberg MH , Brower DL , Shattil SJ . Differences in regulation of Drosophila and vertebrate integrin affinity by talin. Mol Biol Cell 19: 3589‐3598, 2008.
 203. Herman IM , Crisona NJ , Pollard TD . Relation between cell activity and the distribution of cytoplasmic actin and myosin. J Cell Biol 90: 84‐91, 1981.
 204. 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.
 205. Hilfiker‐Kleiner D , Hilfiker A , Fuchs M , Kaminski K , Schaefer A , Schieffer B , Hillmer A , Schmiedl A , Ding Z , Podewski E , Poli V , Schneider MD , Schulz R , Park JK , Wollert KC , Drexler H . Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95: 187‐195, 2004.
 206. Hinz B . Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 127: 526‐537, 2007.
 207. Hinz B . The myofibroblast: Paradigm for a mechanically active cell. J Biomech 43: 146‐155, 2010.
 208. Hinz B . Tissue stiffness, latent TGF‐beta1 activation, and mechanical signal transduction: Implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 11: 120‐126, 2009.
 209. Hinz B , Phan SH , Thannickal VJ , Galli A , Bochaton‐Piallat ML , Gabbiani G . The myofibroblast: One function, multiple origins. Am J Pathol 170: 1807‐1816, 2007.
 210. Hirata H , Tatsumi H , Lim CT , Sokabe M . Force‐dependent vinculin binding to talin in live cells: A crucial step in anchoring the actin cytoskeleton to focal adhesions. Am J Physiol‐Cell Ph 306: C607‐620, 2014.
 211. Holmes JW , Borg TK , Covell JW . Structure and mechanics of healing myocardial infarcts. Annu Rev Biomed Eng 7: 223‐253, 2005.
 212. Holtz J . Pathophysiology of heart failure and the renin‐angiotensin‐system. Basic Res Cardiol 88(Suppl 1): 183‐201, 1993.
 213. Horazdovsky W. Acquisition and selection of the educated. Quintessenz J 21: 817‐820, 1991.
 214. Hotulainen P , Lappalainen P . Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol 173: 383‐394, 2006.
 215. Hsia DA , Mitra SK , Hauck CR , Streblow DN , Nelson JA , Ilic D , Huang S , Li E , Nemerow GR , Leng J , Spencer KS , Cheresh DA , Schlaepfer DD . Differential regulation of cell motility and invasion by FAK. J Cell Biol 160: 753‐767, 2003.
 216. Hu K , Ji L , Applegate KT , Danuser G , Waterman‐Storer CM . Differential transmission of actin motion within focal adhesions. Science 315: 111‐115, 2007.
 217. Huang X , Yang N , Fiore VF , Barker TH , Sun Y , Morris SW , Ding Q , Thannickal VJ , Zhou Y . Matrix stiffness‐induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Resp Cell Mol Biol 47: 340‐348, 2012.
 218. Humphries JD , Wang P , Streuli C , Geiger B , Humphries MJ , Ballestrem C . Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 179: 1043‐1057, 2007.
 219. Humphries MJ . Integrin structure. Biochem Soc Tran 28: 311‐339, 2000.
 220. Husse B , Briest W , Homagk L , Isenberg G , Gekle M . Cyclical mechanical stretch modulates expression of collagen I and collagen III by PKC and tyrosine kinase in cardiac fibroblasts. Am J Physiol Regul Integr Comp Physiol 293: R1898‐R1907, 2007.
 221. Huveneers S , van den Bout I , Sonneveld P , Sancho A , Sonnenberg A , Danen EH . Integrin alpha v beta 3 controls activity and oncogenic potential of primed c‐Src. Cancer Res 67: 2693‐2700, 2007.
 222. Hynes RO . Integrins: A family of cell surface receptors. Cell 48: 549‐554, 1987.
 223. Ilic D , Furuta Y , Kanazawa S , Takeda N , Sobue K , Nakatsuji N , Nomura S , Fujimoto J , Okada M , Yamamoto T . Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK‐deficient mice. Nature 377: 539‐544, 1995.
 224. Ingber DE . Cellular basis of mechanotransduction. Biol Bullet 194: 323‐325; discussion 325‐327, 1998.
 225. Inoue A , Yanagisawa M , Kimura S , Kasuya Y , Miyauchi T , Goto K , Masaki T . The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A 86: 2863‐2867, 1989.
 226. Inoue A , Yanagisawa M , Takuwa Y , Mitsui Y , Kobayashi M , Masaki T . The human preproendothelin‐1 gene. Complete nucleotide sequence and regulation of expression. J Biol Chem 264: 14954‐14959, 1989.
 227. Ito M , Nakano T , Erdodi F , Hartshorne DJ . Myosin phosphatase: Structure, regulation and function. Mol Cell Biochem 259: 197‐209, 2004.
 228. Janmey PA , Wells RG , Assoian RK , McCulloch CA . From tissue mechanics to transcription factors. Differentiation 86: 112‐120, 2013.
 229. Jazbutyte V , Fiedler J , Kneitz S , Galuppo P , Just A , Holzmann A , Bauersachs J , Thum T . MicroRNA‐22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr) 35: 747‐762, 2013.
 230. Jiang X , Chen S , Asara JM , Balk SP . Phosphoinositide 3‐kinase pathway activation in phosphate and tensin homolog (PTEN)‐deficient prostate cancer cells is independent of receptor tyrosine kinases and mediated by the p110beta and p110delta catalytic subunits. J Biol Chem 285: 14980‐14989, 2010.
 231. Kahner BN , Kato H , Banno A , Ginsberg MH , Shattil SJ , Ye F . Kindlins, integrin activation and the regulation of talin recruitment to alphaIIbbeta3. PloS One 7: e34056, 2012.
 232. Kakiashvili E , Speight P , Waheed F , Seth R , Lodyga M , Tanimura S , Kohno M , Rotstein OD , Kapus A , Szaszi K . GEF‐H1 mediates tumor necrosis factor‐alpha‐induced Rho activation and myosin phosphorylation: Role in the regulation of tubular paracellular permeability. J Biol Chem 284: 11454‐11466, 2009.
 233. Kamikura DM , Khoury H , Maroun C , Naujokas MA , Park M . Enhanced transformation by a plasma membrane‐associated met oncoprotein: Activation of a phosphoinositide 3′‐kinase‐dependent autocrine loop involving hyaluronic acid and CD44. Mol Cell Biol 20: 3482‐3496, 2000.
 234. Kandalam V , Basu R , Abraham T , Wang X , Soloway PD , Jaworski DM , Oudit GY , Kassiri Z . TIMP2 deficiency accelerates adverse post‐myocardial infarction remodeling because of enhanced MT1‐MMP activity despite lack of MMP2 activation. Circ Res 106: 796‐808, 2010.
 235. Kanemura H , Iimuro Y , Takeuchi M , Ueki T , Hirano T , Horiguchi K , Asano Y , Fujimoto J . Hepatocyte growth factor gene transfer with naked plasmid DNA ameliorates dimethylnitrosamine‐induced liver fibrosis in rats. Hepatol Res 38: 930‐939, 2008.
 236. Kapur NK , Qiao X , Paruchuri V , Mackey EE , Daly GH , Ughreja K , Morine KJ , Levine J , Aronovitz MJ , Hill NS , Jaffe IZ , Letarte M , Karas RH . Reducing endoglin activity limits calcineurin and TRPC‐6 expression and improves survival in a mouse model of right ventricular pressure overload. J Am Heart Assoc 3: 2014.
 237. Katoh K , Kano Y , Amano M , Kaibuchi K , Fujiwara K . Stress fiber organization regulated by MLCK and Rho‐kinase in cultured human fibroblasts. Am J Physiol‐Cell Ph 280: C1669‐1679, 2001.
 238. Katoh K , Kano Y , Amano M , Onishi H , Kaibuchi K , Fujiwara K . Rho‐kinase–mediated contraction of isolated stress fibers. J Cell Biol 153: 569‐584, 2001.
 239. Katoh K , Kano Y , Fujiwara K . Isolation and in vitro contraction of stress fibers. Method Enzymol 325: 369‐380, 2000.
 240. Katoh K , Kano Y , Masuda M , Onishi H , Fujiwara K . Isolation and contraction of the stress fiber. Mol Biol Cell 9: 1919‐1938, 1998.
 241. Katoh K , Kano Y , Ookawara S . Rho‐kinase dependent organization of stress fibers and focal adhesions in cultured fibroblasts. Genes Cells 12: 623‐638, 2007.
 242. Kavsak P , Rasmussen RK , Causing CG , Bonni S , Zhu H , Thomsen GH , Wrana JL . Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6: 1365‐1375, 2000.
 243. Kawabata S , Usukura J , Morone N , Ito M , Iwamatsu A , Kaibuchi K , Amano M . Interaction of Rho‐kinase with myosin II at stress fibres. Genes Cells 9: 653‐660, 2004.
 244. Kawaguchi M , Takahashi M , Hata T , Kashima Y , Usui F , Morimoto H , Izawa A , Takahashi Y , Masumoto J , Koyama J , Hongo M , Noda T , Nakayama J , Sagara J , Taniguchi S , Ikeda U . Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123: 594‐604, 2011.
 245. Kawano Y , Fukata Y , Oshiro N , Amano M , Nakamura T , Ito M , Matsumura F , Inagaki M , Kaibuchi K . Phosphorylation of myosin‐binding subunit (MBS) of myosin phosphatase by Rho‐kinase in vivo. J Cell Biol 147: 1023‐1038, 1999.
 246. Kelly D , Khan S , Cockerill G , Ng LL , Thompson M , Samani NJ , Squire IB . Circulating stromelysin‐1 (MMP‐3): A novel predictor of LV dysfunction, remodelling and all‐cause mortality after acute myocardial infarction. Eur J Heart Failure 10: 133‐139, 2008.
 247. Kessler E , Takahara K , Biniaminov L , Brusel M , Greenspan DS . Bone morphogenetic protein‐1: The type I procollagen C‐proteinase. Science 271: 360‐362, 1996.
 248. Kida Y , Kobayashi M , Suzuki T , Takeshita A , Okamatsu Y , Hanazawa S , Yasui T , Hasegawa K . Interleukin‐1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase‐1 production via activation of MAPK/AP‐1 and NF‐kappaB in human gingival fibroblasts. Cytokine 29: 159‐168, 2005.
 249. Kiema T , Lad Y , Jiang P , Oxley CL , Baldassarre M , Wegener KL , Campbell ID , Ylanne J , Calderwood DA . The molecular basis of filamin binding to integrins and competition with talin. Mol Cell 21: 337‐347, 2006.
 250. Kim C , Ye F , Ginsberg MH . Regulation of integrin activation. Annu Rev Cell Dev Biol 27: 321‐345, 2011.
 251. Kim H , Nakamura F , Lee W , Hong C , Perez‐Sala D , McCulloch CA . Regulation of cell adhesion to collagen via beta1 integrins is dependent on interactions of filamin A with vimentin and protein kinase C epsilon. Exp Cell Res 316: 1829‐1844, 2010.
 252. Kim H , Sengupta A , Glogauer M , McCulloch CA . Filamin A regulates cell spreading and survival via beta1 integrins. Exp Cell Res 314: 834‐846, 2008.
 253. Kimura K , Ito M , Amano M , Chihara K , Fukata Y , Nakafuku M , Yamamori B , Feng J , Nakano T , Okawa K , Iwamatsu A , Kaibuchi K . Regulation of myosin phosphatase by Rho and Rho‐associated kinase (Rho‐kinase). Science 273: 245‐248, 1996.
 254. Kinoshita T , Ishikawa Y , Arita M , Akishima‐Fukasawa Y , Fujita K , Inomata N , Suzuki T , Namiki A , Mikami T , Ikeda T , Yamazaki J , Ishii T , Akasaka Y . Antifibrotic response of cardiac fibroblasts in hypertensive hearts through enhanced TIMP‐1 expression by basic fibroblast growth factor. Cardiovasc Pathol 23: 92‐100, 2014.
 255. Kishimoto T , Okumura E . In vivo regulation of the entry into M‐phase: Initial activation and nuclear translocation of cyclin B/Cdc2. Prog Cell Cycle Res 3: 241‐249, 1997.
 256. Klein EA , Yin L , Kothapalli D , Castagnino P , Byfield FJ , Xu T , Levental I , Hawthorne E , Janmey PA , Assoian RK . Cell‐cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol 19: 1511‐1518, 2009.
 257. Klemke RL , Leng J , Molander R , Brooks PC , Vuori K , Cheresh DA . CAS/Crk coupling serves as a “molecular switch” for induction of cell migration. J Cell Biol 140: 961‐972, 1998.
 258. Klingbeil CK , Hauck CR , Hsia DA , Jones KC , Reider SR , Schlaepfer DD . Targeting Pyk2 to beta 1‐integrin‐containing focal contacts rescues fibronectin‐stimulated signaling and haptotactic motility defects of focal adhesion kinase‐null cells. J Cell Biol 152: 97‐110, 2001.
 259. Ko KS , Arora PD , McCulloch CA . Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch‐sensitive calcium‐permeable channels. J Biol Chem 276: 35967‐35977, 2001.
 260. Kobielak A , Fuchs E . Alpha‐catenin: At the junction of intercellular adhesion and actin dynamics. Nature Rev Mol Cell Biol 5: 614‐625, 2004.
 261. Koestler SA , Steffen A , Nemethova M , Winterhoff M , Luo N , Holleboom JM , Krupp J , Jacob S , Vinzenz M , Schur F , Schluter K , Gunning PW , Winkler C , Schmeiser C , Faix J , Stradal TE , Small JV , Rottner K . Arp2/3 complex is essential for actin network treadmilling as well as for targeting of capping protein and cofilin. Mol Biol Cell 24: 2861‐2875, 2013.
 262. Koitabashi N , Danner T , Zaiman AL , Pinto YM , Rowell J , Mankowski J , Zhang D , Nakamura T , Takimoto E , Kass DA . Pivotal role of cardiomyocyte TGF‐beta signaling in the murine pathological response to sustained pressure overload. J Clin Invest 121: 2301‐2312, 2011.
 263. Kong‐Beltran M , Stamos J , Wickramasinghe D . The Sema domain of Met is necessary for receptor dimerization and activation. Cancer cell 6: 75‐84, 2004.
 264. Kooistra MR , Dube N , Bos JL . Rap1: A key regulator in cell‐cell junction formation. J Cell Sci 120: 17‐22, 2007.
 265. Koudssi F , Lopez JE , Villegas S , Long CS . Cardiac fibroblasts arrest at the G1/S restriction point in response to interleukin (IL)‐1beta. Evidence for IL‐1beta‐induced hypophosphorylation of the retinoblastoma protein. J Biol Chem 273: 25796‐25803, 1998.
 266. Kozma R , Ahmed S , Best A , Lim L . The Ras‐related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol 15: 1942‐1952, 1995.
 267. Krause M , Dent EW , Bear JE , Loureiro JJ , Gertler FB . Ena/VASP proteins: Regulators of the actin cytoskeleton and cell migration. Annu Rev Cell Dev Biol 19: 541‐564, 2003.
 268. Kumar S , Maxwell IZ , Heisterkamp A , Polte TR , Lele TP , Salanga M , Mazur E , Ingber DE . Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization, and extracellular matrix mechanics. Biophys J 90: 3762‐3773, 2006.
 269. Kuwahara K , Barrientos T , Pipes GC , Li S , Olson EN . Muscle‐specific signaling mechanism that links actin dynamics to serum response factor. Mol Cell Biol 25: 3173‐3181, 2005.
 270. Kuwahara K , Wang Y , McAnally J , Richardson JA , Bassel‐Duby R , Hill JA , Olson EN . TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 116: 3114‐3126, 2006.
 271. Laeremans H , Rensen SS , Ottenheijm HC , Smits JF , Blankesteijn WM . Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts. Cardiovasc Res 87: 514‐523, 2010.
 272. Lafuente EM , van Puijenbroek AA , Krause M , Carman CV , Freeman GJ , Berezovskaya A , Constantine E , Springer TA , Gertler FB , Boussiotis VA . RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1‐GTP and mediates Rap1‐induced adhesion. Dev Cell 7: 585‐595, 2004.
 273. Lamb NJ , Fernandez A , Conti MA , Adelstein R , Glass DB , Welch WJ , Feramisco JR . Regulation of actin microfilament integrity in living nonmuscle cells by the cAMP‐dependent protein kinase and the myosin light chain kinase. J Cell Biol 106: 1955‐1971, 1988.
 274. Lang P , Gesbert F , Delespine‐Carmagnat M , Stancou R , Pouchelet M , Bertoglio J . Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J 15: 510‐519, 1996.
 275. Lappalainen P , Drubin DG . Cofilin promotes rapid actin filament turnover in vivo. Nature 388: 78‐82, 1997.
 276. Lawson C , Lim ST , Uryu S , Chen XL , Calderwood DA , Schlaepfer DD . FAK promotes recruitment of talin to nascent adhesions to control cell motility. J Cell Biol 196: 223‐232, 2012.
 277. Lazard D , Sastre X , Frid MG , Glukhova MA , Thiery JP , Koteliansky VE . Expression of smooth muscle‐specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A 90: 999‐1003, 1993.
 278. Leask A . Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res 106: 1675‐1680, 2010.
 279. Leask A . Targeting the TGFbeta, endothelin‐1 and CCN2 axis to combat fibrosis in scleroderma. Cell Signal 20: 1409‐1414, 2008.
 280. Leask A . TGFbeta, cardiac fibroblasts, and the fibrotic response. Cardiovasc Res 74: 207‐212, 2007.
 281. Leask A , Abraham DJ . TGF‐beta signaling and the fibrotic response. FASEB J 18: 816‐827, 2004.
 282. Leask A , Holmes A , Black CM , Abraham DJ . Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor‐beta 2 in fibroblasts. J Biol Chem 278: 13008‐13015, 2003.
 283. LeBleu VS , Taduri G , O'Connell J , Teng Y , Cooke VG , Woda C , Sugimoto H , Kalluri R . Origin and function of myofibroblasts in kidney fibrosis. Nature Med 19: 1047‐1053, 2013.
 284. Lee AA , Dillmann WH , McCulloch AD , Villarreal FJ . Angiotensin II stimulates the autocrine production of transforming growth factor‐beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol 27: 2347‐2357, 1995.
 285. Lee HS , Lim CJ , Puzon‐McLaughlin W , Shattil SJ , Ginsberg MH . RIAM activates integrins by linking talin to ras GTPase membrane‐targeting sequences. J Biol Chem 284: 5119‐5127, 2009.
 286. Li P , Wang D , Lucas J , Oparil S , Xing D , Cao X , Novak L , Renfrow MB , Chen YF . Atrial natriuretic peptide inhibits transforming growth factor beta‐induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102: 185‐192, 2008.
 287. Li YY , Feldman AM , Sun Y , McTiernan CF . Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 98: 1728‐1734, 1998.
 288. 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.
 289. Li Z , Wang C , Jiao X , Lu Y , Fu M , Quong AA , Dye C , Yang J , Dai M , Ju X , Zhang X , Li A , Burbelo P , Stanley ER , Pestell RG . Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling. Mol Cell Biol 26: 4240‐4256, 2006.
 290. 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.
 291. Lie‐Venema H , van den Akker NM , Bax NA , Winter EM , Maas S , Kekarainen T , Hoeben RC , deRuiter MC , Poelmann RE , Gittenberger‐de Groot AC . Origin, fate, and function of epicardium‐derived cells (EPDCs) in normal and abnormal cardiac development. ScientificWorldJournal 7: 1777‐1798, 2007.
 292. Lim Y , Han I , Jeon J , Park H , Bahk YY , Oh ES . Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts. J Biol Chem 279: 29060‐29065, 2004.
 293. Lim Y , Lim ST , Tomar A , Gardel M , Bernard‐Trifilo JA , Chen XL , Uryu SA , Canete‐Soler R , Zhai J , Lin H , Schlaepfer WW , Nalbant P , Bokoch G , Ilic D , Waterman‐Storer C , Schlaepfer DD . PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol 180: 187‐203, 2008.
 294. Lindsey ML . MMP induction and inhibition in myocardial infarction. Heart Fail Rev 9: 7‐19, 2004.
 295. Liu S , Xu SW , Kennedy L , Pala D , Chen Y , Eastwood M , Carter DE , Black CM , Abraham DJ , Leask A . FAK is required for TGFbeta‐induced JNK phosphorylation in fibroblasts: Implications for acquisition of a matrix‐remodeling phenotype. Mol Biol Cell 18: 2169‐2178, 2007.
 296. 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.
 297. Lo RS , Wotton D , Massague J . Epidermal growth factor signaling via Ras controls the Smad transcriptional co‐repressor TGIF. EMBO J 20: 128‐136, 2001.
 298. Lodish H , Berk A , Zipursky SL , Matsudaira P , Baltimore D , Darnell J . Section 20.4, receptor tyrosine kinases. In: Molecular Cell Biology. New York, NY: W. H. Freeman, 2000.
 299. Lopez‐Casillas F , Wrana JL , Massague J . Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73: 1435‐1444, 1993.
 300. Lundberg AS , Weinberg RA . Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin‐cdk complexes. Mol Cell Biol 18: 753‐761, 1998.
 301. Lutz R , Sakai T , Chiquet M . Pericellular fibronectin is required for RhoA‐dependent responses to cyclic strain in fibroblasts. J Cell Sci 123: 1511‐1521, 2010.
 302. Ma Y , Chiao YA , Zhang J , Manicone AM , Jin YF , Lindsey ML . Matrix metalloproteinase‐28 deletion amplifies inflammatory and extracellular matrix responses to cardiac aging. Microsc Microanal 18: 81‐90, 2012.
 303. Ma Y , Zhang X , Bao H , Mi S , Cai W , Yan H , Wang Q , Wang Z , Yan J , Fan GC , Lindsey ML , Hu Z . Toll‐like receptor (TLR) 2 and TLR4 differentially regulate doxorubicin induced cardiomyopathy in mice. PloS One 7: e40763, 2012.
 304. Mack CP , Somlyo AV , Hautmann M , Somlyo AP , Owens GK . Smooth muscle differentiation marker gene expression is regulated by RhoA‐mediated actin polymerization. J Biol Chem 276: 341‐347, 2001.
 305. Maeda S , Dean DD , Gomez R , Schwartz Z , Boyan BD . The first stage of transforming growth factor beta1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin‐1 (MMP‐3). Calcif Tissue Int 70: 54‐65, 2002.
 306. Maekawa M , Ishizaki T , Boku S , Watanabe N , Fujita A , Iwamatsu A , Obinata T , Ohashi K , Mizuno K , Narumiya S . Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM‐kinase. Science 285: 895‐898, 1999.
 307. Maier S , Lutz R , Gelman L , Sarasa‐Renedo A , Schenk S , Grashoff C , Chiquet M . Tenascin‐C induction by cyclic strain requires integrin‐linked kinase. Biochim Biophys Acta 1783: 1150‐1162, 2008.
 308. Makino N , Sugano M , Satoh S , Oyama J , Maeda T . Peroxisome proliferator‐activated receptor‐gamma ligands attenuate brain natriuretic peptide production and affect remodeling in cardiac fibroblasts in reoxygenation after hypoxia. Cell Biochem Biophys 44: 65‐71, 2006.
 309. Manabe I , Shindo T , Nagai R . Gene expression in fibroblasts and fibrosis: Involvement in cardiac hypertrophy. Circ Res 91: 1103‐1113, 2002.
 310. Manabe R , Ohe N , Maeda T , Fukuda T , Sekiguchi K . Modulation of cell‐adhesive activity of fibronectin by the alternatively spliced EDA segment. J Cell Biol 139: 295‐307, 1997.
 311. Manickam N , Patel M , Griendling KK , Gorin Y , Barnes JL . RhoA/Rho kinase mediates TGF‐beta1‐induced kidney myofibroblast activation through Poldip2/Nox4‐derived reactive oxygen species. Am J Physiol Renal Physiol 307: F159‐171, 2014.
 312. Mann DL , Spinale FG . Activation of matrix metalloproteinases in the failing human heart: Breaking the tie that binds. Circulation 98: 1699‐1702, 1998.
 313. Manser E , Loo TH , Koh CG , Zhao ZS , Chen XQ , Tan L , Tan I , Leung T , Lim L . PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol Cell 1: 183‐192, 1998.
 314. Manso AM , Elsherif L , Kang SM , Ross RS . Integrins, membrane‐type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling. Cardiovasc Res 69: 574‐584, 2006.
 315. Manso AM , Kang SM , Ross RS . Integrins, focal adhesions, and cardiac fibroblasts. J Invest Med 57: 856‐860, 2009.
 316. Martin MM , Buckenberger JA , Jiang J , Malana GE , Knoell DL , Feldman DS , Elton TS . TGF‐beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways. Am J Physiol Lung Cell Mol Physiol 293: L790‐799, 2007.
 317. Martinon F , Mayor A , Tschopp J . The inflammasomes: Guardians of the body. Annu Rev Immunol 27: 229‐265, 2009.
 318. Martos R , Baugh J , Ledwidge M , O'Loughlin C , Conlon C , Patle A , Donnelly SC , McDonald K . Diastolic heart failure: Evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115: 888‐895, 2007.
 319. Masumoto J , Taniguchi S , Ayukawa K , Sarvotham H , Kishino T , Niikawa N , Hidaka E , Katsuyama T , Higuchi T , Sagara J . ASC, a novel 22‐kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL‐60 cells. J Biol Chem 274: 33835‐33838, 1999.
 320. Mayorga M , Bahi N , Ballester M , Comella JX , Sanchis D . Bcl‐2 is a key factor for cardiac fibroblast resistance to programmed cell death. J Biol Chem 279: 34882‐34889, 2004.
 321. McClain PE . Characterization of cardiac muscle collagen. Molecular heterogeneity. J Biol Chem 249: 2303‐2311, 1974.
 322. Meerson FZ . A mechanism of hypertrophy and wear of the myocardium. Am J Cardiol 15: 755‐760, 1965.
 323. Meloche S , Pouyssegur J . The ERK1/2 mitogen‐activated protein kinase pathway as a master regulator of the G1‐ to S‐phase transition. Oncogene 26: 3227‐3239, 2007.
 324. Meran S , Thomas D , Stephens P , Martin J , Bowen T , Phillips A , Steadman R . Involvement of hyaluronan in regulation of fibroblast phenotype. J Biol Chem 282: 25687‐25697, 2007.
 325. Miki H , Miura K , Takenawa T . N‐WASP, a novel actin‐depolymerizing protein, regulates the cortical cytoskeletal rearrangement in a PIP2‐dependent manner downstream of tyrosine kinases. EMBO J 15: 5326‐5335, 1996.
 326. Miki H , Suetsugu S , Takenawa T . WAVE, a novel WASP‐family protein involved in actin reorganization induced by Rac. EMBO J 17: 6932‐6941, 1998.
 327. Miller NL , Lawson C , Chen XL , Lim ST , Schlaepfer DD . Rgnef (p190RhoGEF) knockout inhibits RhoA activity, focal adhesion establishment, and cell motility downstream of integrins. PloS One 7: e37830, 2012.
 328. Minamino T , Miyauchi H , Yoshida T , Tateno K , Kunieda T , Komuro I . Vascular cell senescence and vascular aging. J Mol Cell Cardiol 36: 175‐183, 2004.
 329. Miralles F , Posern G , Zaromytidou AI , Treisman R . Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113: 329‐342, 2003.
 330. Mitchell MD , Laird RE , Brown RD , Long CS . IL‐1beta stimulates rat cardiac fibroblast migration via MAP kinase pathways. Am J Physiol Heart Circ Physiol 292: H1139‐1147, 2007.
 331. Mitra SK , Hanson DA , Schlaepfer DD . Focal adhesion kinase: In command and control of cell motility. Nature Rev Mol Cell Biol 6: 56‐68, 2005.
 332. Miyazono K , Heldin CH . Role for carbohydrate structures in TGF‐beta 1 latency. Nature 338: 158‐160, 1989.
 333. Mochitate K , Pawelek P , Grinnell F . Stress relaxation of contracted collagen gels: Disruption of actin filament bundles, release of cell surface fibronectin, and down‐regulation of DNA and protein synthesis. Exp Cell Res 193: 198‐207, 1991.
 334. Mogilner A , Oster G . Polymer motors: Pushing out the front and pulling up the back. Curr Biol 13: R721‐733, 2003.
 335. 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.
 336. Montanez E , Ussar S , Schifferer M , Bosl M , Zent R , Moser M , Fassler R . Kindlin‐2 controls bidirectional signaling of integrins. Genes Dev 22: 1325‐1330, 2008.
 337. Mookerjee I , Unemori EN , Du XJ , Tregear GW , Samuel CS . Relaxin modulates fibroblast function, collagen production, and matrix metalloproteinase‐2 expression by cardiac fibroblasts. Ann NY Acad Sci 1041: 190‐193, 2005.
 338. Moore L , Fan D , Basu R , Kandalam V , Kassiri Z . Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail Rev 17: 693‐706, 2012.
 339. Morgan DO . Cyclin‐dependent kinases: Engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13: 261‐291, 1997.
 340. Morgan DO . Principles of CDK regulation. Nature 374: 131‐134, 1995.
 341. Morgan DO , Fisher RP , Espinoza FH , Farrell A , Nourse J , Chamberlin H , Jin P . Control of eukaryotic cell cycle progression by phosphorylation of cyclin‐dependent kinases. Cancer J Sci Am 4(Suppl 1): S77‐83, 1998.
 342. Morton DP . Heart rate responses and fluid balance of competitive cross‐country hang gliding pilots. Int J Sports Physiol Perform 5: 55‐63, 2010.
 343. Mulder KM , Morris SL . Activation of p21ras by transforming growth factor beta in epithelial cells. J Biol Chem 267: 5029‐5031, 1992.
 344. Muranyi A , Derkach D , Erdodi F , Kiss A , Ito M , Hartshorne DJ . Phosphorylation of Thr695 and Thr850 on the myosin phosphatase target subunit: Inhibitory effects and occurrence in A7r5 cells. FEBS Lett 579: 6611‐6615, 2005.
 345. Murayama R , Kobayashi M , Takeshita A , Yasui T , Yamamoto M . MAPKs, activator protein‐1 and nuclear factor‐kappaB mediate production of interleukin‐1beta‐stimulated cytokines, prostaglandin E(2) and MMP‐1 in human periodontal ligament cells. J Periodont Res 46: 568‐575, 2011.
 346. Murphy‐Ullrich JE , Poczatek M . Activation of latent TGF‐beta by thrombospondin‐1: Mechanisms and physiology. Cytokine Growth Factor Rev 11: 59‐69, 2000.
 347. Nagahama KY , Togo S , Holz O , Magnussen H , Liu X , Seyama K , Takahashi K , Rennard SI . Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins‐3. Am J Resp Cell Mol Biol 49: 582‐591, 2013.
 348. Nakamoto T , Sakai R , Ozawa K , Yazaki Y , Hirai H . Direct binding of C‐terminal region of p130Cas to SH2 and SH3 domains of Src kinase. J Biol Chem 271: 8959‐8965, 1996.
 349. Nakao A , Afrakhte M , Moren A , Nakayama T , Christian JL , Heuchel R , Itoh S , Kawabata M , Heldin NE , Heldin CH , ten Dijke P . Identification of Smad7, a TGFbeta‐inducible antagonist of TGF‐beta signalling. Nature 389: 631‐635, 1997.
 350. Nakao A , Imamura T , Souchelnytskyi S , Kawabata M , Ishisaki A , Oeda E , Tamaki K , Hanai J , Heldin CH , Miyazono K , ten Dijke P . TGF‐beta receptor‐mediated signalling through Smad2, Smad3 and Smad4. EMBO J 16: 5353‐5362, 1997.
 351. Nayal A , Webb DJ , Horwitz AF . Talin: An emerging focal point of adhesion dynamics. Curr Opin Cell Biol 16: 94‐98, 2004.
 352. Nevins JR , DeGregori J , Jakoi L , Leone G . Functional analysis of E2F transcription factor. Method Enzymol 283: 205‐219, 1997.
 353. Nevins JR , Leone G , DeGregori J , Jakoi L . Role of the Rb/E2F pathway in cell growth control. J Cell Physiol 173: 233‐236, 1997.
 354. Nigg EA . Mitotic kinases as regulators of cell division and its checkpoints. Nature Rev Mol Cell Biol 2: 21‐32, 2001.
 355. Nimnual AS , Taylor LJ , Bar‐Sagi D . Redox‐dependent downregulation of Rho by Rac. Nat Cell Biol 5: 236‐241, 2003.
 356. Nishida M , Onohara N , Sato Y , Suda R , Ogushi M , Tanabe S , Inoue R , Mori Y , Kurose H . Galpha12/13‐mediated up‐regulation of TRPC6 negatively regulates endothelin‐1‐induced cardiac myofibroblast formation and collagen synthesis through nuclear factor of activated T cells activation. J Biol Chem 282: 23117‐23128, 2007.
 357. Nobes CD , Hall A . Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144: 1235‐1244, 1999.
 358. Nobes CD , Hall A . Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81: 53‐62, 1995.
 359. Numata T , Shimizu T , Okada Y . TRPM7 is a stretch‐ and swelling‐activated cation channel involved in volume regulation in human epithelial cells. Am J Physiol‐Cell Ph 292: C460‐467, 2007.
 360. O'Neill GM , Fashena SJ , Golemis EA . Integrin signalling: A new Cas(t) of characters enters the stage. Trends Cell Biol 10: 111‐119, 2000.
 361. Oakes PW , Beckham Y , Stricker J , Gardel ML . Tension is required but not sufficient for focal adhesion maturation without a stress fiber template. J Cell Biol 196: 363‐374, 2012.
 362. Ogunjimi AA , Briant DJ , Pece‐Barbara N , Le Roy C , Di Guglielmo GM , Kavsak P , Rasmussen RK , Seet BT , Sicheri F , Wrana JL . Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell 19: 297‐308, 2005.
 363. Oliferenko S , Kaverina I , Small JV , Huber LA . Hyaluronic acid (HA) binding to CD44 activates Rac1 and induces lamellipodia outgrowth. J Cell Biol 148: 1159‐1164, 2000.
 364. Olson ER , Naugle JE , Zhang X , Bomser JA , Meszaros JG . Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol Heart Circ Physiol 288: H1131‐1138, 2005.
 365. Olson ER , Shamhart PE , Naugle JE , Meszaros JG . Angiotensin II‐induced extracellular signal‐regulated kinase 1/2 activation is mediated by protein kinase Cdelta and intracellular calcium in adult rat cardiac fibroblasts. Hypertension 51: 704‐711, 2008.
 366. Olson MF , Ashworth A , Hall A . An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science 269: 1270‐1272, 1995.
 367. Onichtchouk D , Chen YG , Dosch R , Gawantka V , Delius H , Massague J , Niehrs C . Silencing of TGF‐beta signalling by the pseudoreceptor BAMBI. Nature 401: 480‐485, 1999.
 368. Orlowski RZ , Small GW , Shi YY . Evidence that inhibition of p44/42 mitogen‐activated protein kinase signaling is a factor in proteasome inhibitor‐mediated apoptosis. J Biol Chem 277: 27864‐27871, 2002.
 369. Otey CA , Carpen O . Alpha‐actinin revisited: A fresh look at an old player. Cell Motil Cytoskeleton 58: 104‐111, 2004.
 370. Oxley CL , Anthis NJ , Lowe ED , Vakonakis I , Campbell ID , Wegener KL . An integrin phosphorylation switch: The effect of beta3 integrin tail phosphorylation on Dok1 and talin binding. J Biol Chem 283: 5420‐5426, 2008.
 371. Padrick SB , Rosen MK . Physical mechanisms of signal integration by WASP family proteins. Annual review of biochemistry 79: 707‐735, 2010.
 372. Palazzo AF , Cook TA , Alberts AS , Gundersen GG . mDia mediates Rho‐regulated formation and orientation of stable microtubules. Nat Cell Biol 3: 723‐729, 2001.
 373. Palazzo AF , Eng CH , Schlaepfer DD , Marcantonio EE , Gundersen GG . Localized stabilization of microtubules by integrin‐ and FAK‐facilitated Rho signaling. Science 303: 836‐839, 2004.
 374. Palmer JN , Hartogensis WE , Patten M , Fortuin FD , Long CS . Interleukin‐1 beta induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture. J Clin Invest 95: 2555‐2564, 1995.
 375. Pan CH , Wen CH , Lin CS . Interplay of angiotensin II and angiotensin(1‐7) in the regulation of matrix metalloproteinases of human cardiocytes. Exp Physiol 93: 599‐612, 2008.
 376. Pantaloni D , Carlier MF . How profilin promotes actin filament assembly in the presence of thymosin beta 4. Cell 75: 1007‐1014, 1993.
 377. Parker KK , Ingber DE . Extracellular matrix, mechanotransduction and structural hierarchies in heart tissue engineering. Philos Trans R Soc Lond B, Biol Sci 362: 1267‐1279, 2007.
 378. Parsons JT . Focal adhesion kinase: The first ten years. J Cell Sci 116: 1409‐1416, 2003.
 379. Paszek MJ , Zahir N , Johnson KR , Lakins JN , Rozenberg GI , Gefen A , Reinhart‐King CA , Margulies SS , Dembo M , Boettiger D , Hammer DA , Weaver VM . Tensional homeostasis and the malignant phenotype. Cancer Cell 8: 241‐254, 2005.
 380. Patel A , Sharif‐Naeini R , Folgering JR , Bichet D , Duprat F , Honore E . Canonical TRP channels and mechanotransduction: From physiology to disease states. Pflugers Arch 460: 571‐581, 2010.
 381. Pedersen SF , Nilius B . Transient receptor potential channels in mechanosensing and cell volume regulation. Method Enzymol 428: 183‐207, 2007.
 382. Pelech SL , Charest DL , Mordret GP , Siow YL , Palaty C , Campbell D , Charlton L , Samiei M , Sanghera JS . Networking with mitogen‐activated protein kinases. Mol Cell Biochem 127‐128: 157‐169, 1993.
 383. Pelham RJ, Jr. , Wang Y . Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci U S A 94: 13661‐13665, 1997.
 384. Pelham RJ, Jr. , Wang Y . High resolution detection of mechanical forces exerted by locomoting fibroblasts on the substrate. Mol Biol Cell 10: 935‐945, 1999.
 385. Peterson LJ , Rajfur Z , Maddox AS , Freel CD , Chen Y , Edlund M , Otey C , Burridge K . Simultaneous stretching and contraction of stress fibers in vivo. Mol Biol Cell 15: 3497‐3508, 2004.
 386. Petit V , Thiery JP . Focal adhesions: Structure and dynamics. Biol Cell 92: 477‐494, 2000
 387. Petrich BG . Talin‐dependent integrin signalling in vivo. Thrombosis and haemostasis 101: 1020‐1024, 2009.
 388. 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.
 389. Petrov VV , Fagard RH , Lijnen PJ . Transforming growth factor‐beta(1) induces angiotensin‐converting enzyme synthesis in rat cardiac fibroblasts during their differentiation to myofibroblasts. J Renin Angiotensin Aldosterone Syst 1: 342‐352, 2000.
 390. Phan SH . Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5: 334‐337, 2008.
 391. Pillai MS , Sapna S , Shivakumar K . p38 MAPK regulates G1‐S transition in hypoxic cardiac fibroblasts. Int J Biochem Cell Biol 43: 919‐927, 2011.
 392. Pinto VI , Senini VW , Wang Y , Kazembe MP , McCulloch CA . Filamin A protects cells against force‐induced apoptosis by stabilizing talin‐ and vinculin‐containing cell adhesions. FASEB J 28: 453‐463, 2014.
 393. Pipes GC , Creemers EE , Olson EN . The myocardin family of transcriptional coactivators: Versatile regulators of cell growth, migration, and myogenesis. Genes Dev 20: 1545‐1556, 2006.
 394. Ponti A , Machacek M , Gupton SL , Waterman‐Storer CM , Danuser G . Two distinct actin networks drive the protrusion of migrating cells. Science 305: 1782‐1786, 2004.
 395. Porter KE , Turner NA . Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacol Ther 123: 255‐278, 2009.
 396. Porter KE , Turner NA , O'Regan DJ , Ball SG . Tumor necrosis factor alpha induces human atrial myofibroblast proliferation, invasion and MMP‐9 secretion: Inhibition by simvastatin. Cardiovasc Res 64: 507‐515, 2004.
 397. Powell SR , Wang P , Katzeff H , Shringarpure R , Teoh C , Khaliulin I , Das DK , Davies KJ , Schwalb H . Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: Essential role of the proteasome. Antioxid Redox Signal 7: 538‐546, 2005.
 398. Prager‐Khoutorsky M , Lichtenstein A , Krishnan R , Rajendran K , Mayo A , Kam Z , Geiger B , Bershadsky AD . Fibroblast polarization is a matrix‐rigidity‐dependent process controlled by focal adhesion mechanosensing. Nat Cell Biol 13: 1457‐1465, 2011.
 399. Pramod S , Shivakumar K . Mechanisms in cardiac fibroblast growth: An obligate role for Skp2 and FOXO3a in ERK1/2 MAPK‐dependent regulation of p27kip1. Am J Physiol Heart Circ Physiol 306: H844‐855, 2014.
 400. Qiu P , Feng XH , Li L . Interaction of Smad3 and SRF‐associated complex mediates TGF‐beta1 signals to regulate SM22 transcription during myofibroblast differentiation. J Mol Cell Cardiol 35: 1407‐1420, 2003.
 401. Raffetto JD , Khalil RA . Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 75: 346‐359, 2008.
 402. Rajkumar VS , Howell K , Csiszar K , Denton CP , Black CM , Abraham DJ . Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 7: R1113‐1123, 2005.
 403. Reddig PJ , Juliano RL . Clinging to life: Cell to matrix adhesion and cell survival. Cancer Metast Rev 24: 425‐439, 2005.
 404. Redondo J , Bishop JE , Wilkins MR . Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts. Br J Pharmacol 124: 1455‐1462, 1998.
 405. Ren XD , Kiosses WB , Schwartz MA . Regulation of the small GTP‐binding protein Rho by cell adhesion and the cytoskeleton. EMBO J 18: 578‐585, 1999.
 406. Ren XD , Wang R , Li Q , Kahek LA , Kaibuchi K , Clark RA . Disruption of Rho signal transduction upon cell detachment. J Cell Sci 117: 3511‐3518, 2004.
 407. Riddick N , Ohtani K , Surks HK . Targeting by myosin phosphatase‐RhoA interacting protein mediates RhoA/ROCK regulation of myosin phosphatase. J Cell Biochem 103: 1158‐1170, 2008.
 408. Ridley AJ , Hall A . Signal transduction pathways regulating Rho‐mediated stress fibre formation: Requirement for a tyrosine kinase. EMBO J 13: 2600‐2610, 1994.
 409. Ridley AJ , Hall A . The small GTP‐binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389‐399, 1992.
 410. Ridley AJ , Paterson HF , Johnston CL , Diekmann D , Hall A . The small GTP‐binding protein rac regulates growth factor‐induced membrane ruffling. Cell 70: 401‐410, 1992.
 411. Ridley AJ , Schwartz MA , Burridge K , Firtel RA , Ginsberg MH , Borisy G , Parsons JT , Horwitz AR . Cell migration: Integrating signals from front to back. Science 302: 1704‐1709, 2003.
 412. Riveline D , Zamir E , Balaban NQ , Schwarz US , Ishizaki T , Narumiya S , Kam Z , Geiger B , Bershadsky AD . Focal contacts as mechanosensors: Externally applied local mechanical force induces growth of focal contacts by an mDia1‐dependent and ROCK‐independent mechanism. J Cell Biol 153: 1175‐1186, 2001.
 413. Roca‐Cusachs P , del Rio A , Puklin‐Faucher E , Gauthier NC , Biais N , Sheetz MP . Integrin‐dependent force transmission to the extracellular matrix by alpha‐actinin triggers adhesion maturation. Proc Natl Acad Sci U S A 110: E1361‐1370, 2013.
 414. Rodriguez‐Vita J , Sanchez‐Lopez E , Esteban V , Ruperez M , Egido J , Ruiz‐Ortega M . Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor‐beta‐independent mechanism. Circulation 111: 2509‐2517, 2005.
 415. Romer LH , Birukov KG , Garcia JG . Focal adhesions: Paradigm for a signaling nexus. Circ Res 98: 606‐616, 2006.
 416. Ronnov‐Jessen L , Petersen OW . Induction of alpha‐smooth muscle actin by transforming growth factor‐beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68: 696‐707, 1993.
 417. Rosenkranz AC , Woods RL , Dusting GJ , Ritchie RH . Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: Importance of cyclic GMP. Cardiovasc Res 57: 515‐522, 2003.
 418. Rottner K , Hall A , Small JV . Interplay between Rac and Rho in the control of substrate contact dynamics. Curr Biol 9: 640‐648, 1999.
 419. Sadoshima J , Izumo S . Signal transduction pathways of angiotensin II–induced c‐fos gene expression in cardiac myocytes in vitro. Roles of phospholipid‐derived second messengers. Circ Res 73: 424‐438, 1993.
 420. Saharinen J , Keski‐Oja J . Specific sequence motif of 8‐Cys repeats of TGF‐beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF‐beta. Mol Biol Cell 11: 2691‐2704, 2000.
 421. Saltel F , Mortier E , Hytonen VP , Jacquier MC , Zimmermann P , Vogel V , Liu W , Wehrle‐Haller B . New PI(4,5)P2‐ and membrane proximal integrin‐binding motifs in the talin head control beta3‐integrin clustering. J Cell Biol 187: 715‐731, 2009.
 422. Sanders MA , Basson MD . p130cas but not paxillin is essential for Caco‐2 intestinal epithelial cell spreading and migration on collagen IV. J Biol Chem 280: 23516‐23522, 2005.
 423. Santamaria‐Kisiel L , Rintala‐Dempsey AC , Shaw GS . Calcium‐dependent and ‐independent interactions of the S100 protein family. Biochem J 396: 201‐214, 2006.
 424. Santander C , Brandan E . Betaglycan induces TGF‐beta signaling in a ligand‐independent manner, through activation of the p38 pathway. Cell Signal 18: 1482‐1491, 2006.
 425. 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.
 426. Sappino AP , Schurch W , Gabbiani G . Differentiation repertoire of fibroblastic cells: Expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest 63: 144‐161, 1990.
 427. Sarasa‐Renedo A , Tunc‐Civelek V , Chiquet M . Role of RhoA/ROCK‐dependent actin contractility in the induction of tenascin‐C by cyclic tensile strain. Exp Cell Res 312: 1361‐1370, 2006.
 428. Sato Y , Kataoka K , Matsumori A , Sasayama S , Yamada T , Ito H , Takatsu Y . Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy. Heart 78: 505‐508, 1997.
 429. Sauzeau V , Le Jeune H , Cario‐Toumaniantz C , Smolenski A , Lohmann SM , Bertoglio J , Chardin P , Pacaud P , Loirand G . Cyclic GMP‐dependent protein kinase signaling pathway inhibits RhoA‐induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 275: 21722‐21729, 2000.
 430. Savvatis K , Pappritz K , Becher PM , Lindner D , Zietsch C , Volk HD , Westermann D , Schultheiss HP , Tschope C . Interleukin‐23 deficiency leads to impaired wound healing and adverse prognosis after myocardial infarction. Circ Heart Fail 7: 161‐171, 2014.
 431. Sawada Y , Tamada M , Dubin‐Thaler BJ , Cherniavskaya O , Sakai R , Tanaka S , Sheetz MP . Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell 127: 1015‐1026, 2006.
 432. Sawai H , Okada Y , Funahashi H , Matsuo Y , Takahashi H , Takeyama H , Manabe T . Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal‐regulated kinase‐1/2 signaling pathway activation. Mol Cancer 4: 37, 2005.
 433. Saxena A , Chen W , Su Y , Rai V , Uche OU , Li N , Frangogiannis NG . IL‐1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J Immunol 191: 4838‐4848, 2013.
 434. Schalla S , Bekkers SC , Dennert R , van Suylen RJ , Waltenberger J , Leiner T , Wildberger J , Crijns HJ , Heymans S . Replacement and reactive myocardial fibrosis in idiopathic dilated cardiomyopathy: Comparison of magnetic resonance imaging with right ventricular biopsy. Eur J Heart Fail 12: 227‐231, 2010.
 435. Schaller MD . Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 1540: 1‐21, 2001.
 436. Schaller MD , Hildebrand JD , Shannon JD , Fox JW , Vines RR , Parsons JT . Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2‐dependent binding of pp60src. Mol Cell Biol 14: 1680‐1688, 1994.
 437. Schaller MD , Parsons JT . pp125FAK‐dependent tyrosine phosphorylation of paxillin creates a high‐affinity binding site for Crk. Mol Cell Biol 15: 2635‐2645, 1995.
 438. Schlaepfer DD , Broome MA , Hunter T . Fibronectin‐stimulated signaling from a focal adhesion kinase‐c‐Src complex: Involvement of the Grb2, p130cas, and Nck adaptor proteins. Mol Cell Biol 17: 1702‐1713, 1997.
 439. Schlaepfer DD , Hauck CR , Sieg DJ . Signaling through focal adhesion kinase. Prog Biophys Mol Bio 71: 435‐478, 1999.
 440. Schlaepfer DD , Jones KC , Hunter T . Multiple Grb2‐mediated integrin‐stimulated signaling pathways to ERK2/mitogen‐activated protein kinase: Summation of both c‐Src‐ and focal adhesion kinase‐initiated tyrosine phosphorylation events. Mol Cell Biol 18: 2571‐2585, 1998.
 441. Schoppet M , Chavakis T , Al‐Fakhri N , Kanse SM , Preissner KT . Molecular interactions and functional interference between vitronectin and transforming growth factor‐beta. Lab Invest 82: 37‐46, 2002.
 442. Schor SL , Ellis I , Dolman C , Banyard J , Humphries MJ , Mosher DF , Grey AM , Mould AP , Sottile J , Schor AM . Substratum‐dependent stimulation of fibroblast migration by the gelatin‐binding domain of fibronectin. J Cell Sci 109(Pt 10): 2581‐2590, 1996.
 443. Schram K , Ganguly R , No EK , Fang X , Thong FS , Sweeney G . Regulation of MT1‐MMP and MMP‐2 by leptin in cardiac fibroblasts involves Rho/ROCK‐dependent actin cytoskeletal reorganization and leads to enhanced cell migration. Endocrinology 152: 2037‐2047, 2011.
 444. Schram K , Wong MM , Palanivel R , No EK , Dixon IM , Sweeney G . Increased expression and cell surface localization of MT1‐MMP plays a role in stimulation of MMP‐2 activity by leptin in neonatal rat cardiac myofibroblasts. J Mol Cell Cardiol 44: 874‐881, 2008.
 445. Schwartz MA , DeSimone DW . Cell adhesion receptors in mechanotransduction. Curr Opin Cell Biol 20: 551‐556, 2008.
 446. Sechi AS , Wehland J . ENA/VASP proteins: Multifunctional regulators of actin cytoskeleton dynamics. Front Biosci 9: 1294‐1310, 2004.
 447. Serhan CN . Novel lipid mediators and resolution mechanisms in acute inflammation: To resolve or not? Am J Pathol 177: 1576‐1591, 2010.
 448. 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.
 449. Shamhart PE , Meszaros JG . Non‐fibrillar collagens: Key mediators of post‐infarction cardiac remodeling? J Mol Cell Cardiol 48: 530‐537, 2010.
 450. Shao H , Wang JH , Pollak MR , Wells A . alpha‐actinin‐4 is essential for maintaining the spreading, motility and contractility of fibroblasts. PloS One 5: e13921, 2010.
 451. Sharma A , Mayer BJ . Phosphorylation of p130Cas initiates Rac activation and membrane ruffling. BMC Cell Biol 9: 50, 2008.
 452. Shattil SJ . Integrins and Src: Dynamic duo of adhesion signaling. Trends Cell Biol 15: 399‐403, 2005.
 453. Shattil SJ , Kim C , Ginsberg MH . The final steps of integrin activation: The end game. Nature Rev Mol Cell Biol 11: 288‐300, 2010.
 454. Shen XM , Wu YP , Feng YB , Luo ML , Du XL , Zhang Y , Cai Y , Xu X , Han YL , Zhang X , Zhan QM , Wang MR . Interaction of MT1‐MMP and laminin‐5gamma2 chain correlates with metastasis and invasiveness in human esophageal squamous cell carcinoma. Clin Exp Metastas 24: 541‐550, 2007.
 455. Sherr CJ . Cancer cell cycles. Science 274: 1672‐1677, 1996.
 456. Sherr CJ , Roberts JM . CDK inhibitors: Positive and negative regulators of G1‐phase progression. Genes Dev 13: 1501‐1512, 1999.
 457. Shi‐wen X , Kennedy L , Renzoni EA , Bou‐Gharios G , du Bois RM , Black CM , Denton CP , Abraham DJ , Leask A . Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts. Arthritis Rheum 56: 4189‐4194, 2007.
 458. Shi‐wen X , Parapuram SK , Pala D , Chen Y , Carter DE , Eastwood M , Denton CP , Abraham DJ , Leask A . Requirement of transforming growth factor beta‐activated kinase 1 for transforming growth factor beta‐induced alpha‐smooth muscle actin expression and extracellular matrix contraction in fibroblasts. Arthritis Rheum 60: 234‐241, 2009.
 459. Shifrin Y , Pinto VI , Hassanali A , Arora PD , McCulloch CA . Force‐induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A. Biochem J 445: 57‐67, 2012.
 460. Siddesha JM , Valente AJ , Sakamuri SS , Yoshida T , Gardner JD , Somanna N , Takahashi C , Noda M , Chandrasekar B . Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK. J Mol Cell Cardiol 65: 9‐18, 2013.
 461. Sieg DJ , Hauck CR , Ilic D , Klingbeil CK , Schaefer E , Damsky CH , Schlaepfer DD . FAK integrates growth‐factor and integrin signals to promote cell migration. Nat Cell Biol 2: 249‐256, 2000.
 462. Sieg DJ , Hauck CR , Schlaepfer DD . Required role of focal adhesion kinase (FAK) for integrin‐stimulated cell migration. J Cell Sci 112(Pt 16): 2677‐2691, 1999.
 463. Simm A , Nestler M , Hoppe V . Mitogenic effect of PDGF‐AA on cardiac fibroblasts. Basic Res Cardiol 93(Suppl 3): 40‐43, 1998.
 464. Simm A , Nestler M , Hoppe V . PDGF‐AA, a potent mitogen for cardiac fibroblasts from adult rats. J Mol Cell Cardiol 29: 357‐368, 1997.
 465. Simonson WT , Franco SJ , Huttenlocher A . Talin1 regulates TCR‐mediated LFA‐1 function. J Immunol 177: 7707‐7714, 2006.
 466. Simpson DG , Majeski M , Borg TK , Terracio L . Regulation of cardiac myocyte protein turnover and myofibrillar structure in vitro by specific directions of stretch. Circ Res 85: e59‐69, 1999.
 467. Singh RB , Chohan PK , Dhalla NS , Netticadan T . The sarcoplasmic reticulum proteins are targets for calpain action in the ischemic‐reperfused heart. J Mol Cell Cardiol 37: 101‐110, 2004.
 468. Siwik DA , Chang DL , Colucci WS . Interleukin‐1beta and tumor necrosis factor‐alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res 86: 1259‐1265, 2000.
 469. Siwik DA , Pagano PJ , Colucci WS . Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol‐Cell Ph 280: C53‐60, 2001.
 470. 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.
 471. Small JV , Anderson K , Rottner K . Actin and the coordination of protrusion, attachment and retraction in cell crawling. Bioscience Rep 16: 351‐368, 1996.
 472. Songyang Z , Shoelson SE , Chaudhuri M , Gish G , Pawson T , Haser WG , King F , Roberts T , Ratnofsky S , Lechleider RJ , et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72: 767‐778, 1993.
 473. Soranno T , Bell E . Cytostructural dynamics of spreading and translocating cells. J Cell Biol 95: 127‐136, 1982.
 474. Sottile J , Hocking DC . Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell‐matrix adhesions. Mol Biol Cell 13: 3546‐3559, 2002.
 475. Spinale FG . Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiol Rev 87: 1285‐1342, 2007.
 476. Spinale FG , Coker ML , Heung LJ , Bond BR , Gunasinghe HR , Etoh T , Goldberg AT , Zellner JL , Crumbley AJ . A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102: 1944‐1949, 2000.
 477. Stacy LB , Yu Q , Horak K , Larson DF . Effect of angiotensin II on primary cardiac fibroblast matrix metalloproteinase activities. Perfusion 22: 51‐55, 2007.
 478. Stamos J , Lazarus RA , Yao X , Kirchhofer D , Wiesmann C . Crystal structure of the HGF beta‐chain in complex with the Sema domain of the Met receptor. EMBO J 23: 2325‐2335, 2004.
 479. Staudinger LA , Spano SJ , Lee W , Coelho N , Rajshankar D , Bendeck MP , Moriarty T , McCulloch CA . Interactions between the discoidin domain receptor 1 and beta1 integrin regulate attachment to collagen. Biol Open 2: 1148‐1159, 2013.
 480. Stawowy P , Margeta C , Kallisch H , Seidah NG , Chretien M , Fleck E , Graf K . Regulation of matrix metalloproteinase MT1‐MMP/MMP‐2 in cardiac fibroblasts by TGF‐beta1 involves furin‐convertase. Cardiovasc Res 63: 87‐97, 2004.
 481. Steffen A , Ladwein M , Dimchev GA , Hein A , Schwenkmezger L , Arens S , Ladwein KI , Margit Holleboom J , Schur F , Victor Small J , Schwarz J , Gerhard R , Faix J , Stradal TE , Brakebusch C , Rottner K . Rac function is crucial for cell migration but is not required for spreading and focal adhesion formation. J Cell Sci 126: 4572‐4588, 2013.
 482. Steffensen B , Wallon UM , Overall CM . Extracellular matrix binding properties of recombinant fibronectin type II‐like modules of human 72‐kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen. J Biol Chem 270: 11555‐11566, 1995.
 483. Stillman B . Cell cycle control of DNA replication. Science 274: 1659‐1664, 1996.
 484. Stocks SZ , Taylor SM , Shiels IA . Transforming growth factor‐beta1 induces alpha‐smooth muscle actin expression and fibronectin synthesis in cultured human retinal pigment epithelial cells. Clin Experiment Ophthalmol 29: 33‐37, 2001.
 485. Streblow DN , Vomaske J , Smith P , Melnychuk R , Hall L , Pancheva D , Smit M , Casarosa P , Schlaepfer DD , Nelson JA . Human cytomegalovirus chemokine receptor US28‐induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J Biol Chem 278: 50456‐50465, 2003.
 486. Sun Y , Weber KT . Infarct scar: A dynamic tissue. Cardiovasc Res 46: 250‐256, 2000.
 487. Suraneni P , Rubinstein B , Unruh JR , Durnin M , Hanein D , Li R . The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J Cell Biol 197: 239‐251, 2012.
 488. 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.
 489. Tadokoro S , Shattil SJ , Eto K , Tai V , Liddington RC , de Pereda JM , Ginsberg MH , Calderwood DA . Talin binding to integrin beta tails: A final common step in integrin activation. Science 302: 103‐106, 2003.
 490. Taipale J , Miyazono K , Heldin CH , Keski‐Oja J . Latent transforming growth factor‐beta 1 associates to fibroblast extracellular matrix via latent TGF‐beta binding protein. J Cell Biol 124: 171‐181, 1994.
 491. Takahra T , Smart DE , Oakley F , Mann DA . Induction of myofibroblast MMP‐9 transcription in three‐dimensional collagen I gel cultures: Regulation by NF‐kappaB, AP‐1 and Sp1. Int J Biochem Cell Biol 36: 353‐363, 2004.
 492. Takeda N , Manabe I , Uchino Y , Eguchi K , Matsumoto S , Nishimura S , Shindo T , Sano M , Otsu K , Snider P , Conway SJ , Nagai R . Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120: 254‐265, 2010.
 493. Takemura G , Ohno M , Hayakawa Y , Misao J , Kanoh M , Ohno A , Uno Y , Minatoguchi S , Fujiwara T , Fujiwara H . Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction. Circ Res 82: 1130‐1138, 1998.
 494. Takenawa T , Suetsugu S . The WASP‐WAVE protein network: Connecting the membrane to the cytoskeleton. Nature Rev Mol Cell Biol 8: 37‐48, 2007.
 495. Tamada M , Sheetz MP , Sawada Y . Activation of a signaling cascade by cytoskeleton stretch. Dev Cell 7: 709‐718, 2004.
 496. Tamaki Y , Iwanaga Y , Niizuma S , Kawashima T , Kato T , Inuzuka Y , Horie T , Morooka H , Takase T , Akahashi Y , Kobuke K , Ono K , Shioi T , Sheikh SP , Ambartsumian N , Lukanidin E , Koshimizu TA , Miyazaki S , Kimura T . Metastasis‐associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. J Mol Cell Cardiol 57: 72‐81, 2013.
 497. ten Dijke P , Arthur HM . Extracellular control of TGFbeta signalling in vascular development and disease. Nature Rev Mol Cell Biol 8: 857‐869, 2007.
 498. ten Klooster JP , Jaffer ZM , Chernoff J , Hordijk PL . Targeting and activation of Rac1 are mediated by the exchange factor beta‐Pix. J Cell Biol 172: 759‐769, 2006.
 499. Tetsu O , McCormick F . Beta‐catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422‐426, 1999.
 500. Theriot JA . Accelerating on a treadmill: ADF/cofilin promotes rapid actin filament turnover in the dynamic cytoskeleton. J Cell Biol 136: 1165‐1168, 1997.
 501. Thievessen I , Thompson PM , Berlemont S , Plevock KM , Plotnikov SV , Zemljic‐Harpf A , Ross RS , Davidson MW , Danuser G , Campbell SL , Waterman CM . Vinculin‐actin interaction couples actin retrograde flow to focal adhesions, but is dispensable for focal adhesion growth. J Cell Biol 202: 163‐177, 2013.
 502. Thodeti CK , Paruchuri S , Meszaros JG . A TRP to cardiac fibroblast differentiation. Channels (Austin) 7: 211‐214, 2013.
 503. Thomas CV , Coker ML , Zellner JL , Handy JR , Crumbley AJ, III , Spinale FG . Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end‐stage dilated cardiomyopathy. Circulation 97: 1708‐1715, 1998.
 504. Thum T , Galuppo P , Wolf C , Fiedler J , Kneitz S , van Laake LW , Doevendans PA , Mummery CL , Borlak J , Haverich A , Gross C , Engelhardt S , Ertl G , Bauersachs J . MicroRNAs in the human heart: A clue to fetal gene reprogramming in heart failure. Circulation 116: 258‐267, 2007.
 505. 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.
 506. Tokiwa G , Dikic I , Lev S , Schlessinger J . Activation of Pyk2 by stress signals and coupling with JNK signaling pathway. Science 273: 792‐794, 1996.
 507. Tomar A , Lim ST , Lim Y , Schlaepfer DD . A FAK‐p120RasGAP‐p190RhoGAP complex regulates polarity in migrating cells. J Cell Sci 122: 1852‐1862, 2009.
 508. Tomasek JJ , Gabbiani G , Hinz B , Chaponnier C , Brown RA . Myofibroblasts and mechano‐regulation of connective tissue remodelling. Nature Rev Mol Cell Biol 3: 349‐363, 2002.
 509. Tomasek JJ , Haaksma CJ , Eddy RJ , Vaughan MB . Fibroblast contraction occurs on release of tension in attached collagen lattices: Dependency on an organized actin cytoskeleton and serum. Anat Rec 232: 359‐368, 1992.
 510. Toole BP . Hyaluronan is not just a goo! J Clin Invest 106: 335‐336, 2000.
 511. Torsoni AS , Marin TM , Velloso LA , Franchini KG . RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. Am J Physiol Heart Circ Physiol 289: H1488‐1496, 2005.
 512. Totsukawa G , Wu Y , Sasaki Y , Hartshorne DJ , Yamakita Y , Yamashiro S , Matsumura F . Distinct roles of MLCK and ROCK in the regulation of membrane protrusions and focal adhesion dynamics during cell migration of fibroblasts. J Cell Biol 164: 427‐439, 2004.
 513. Totsukawa G , Yamakita Y , Yamashiro S , Hartshorne DJ , Sasaki Y , Matsumura F . Distinct roles of ROCK (Rho‐kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J Cell Biol 150: 797‐806, 2000.
 514. Trombetta‐eSilva J , Eadie EP , Zhang Y , Norris RA , Borg TK , Bradshaw AD . The effects of age and the expression of SPARC on extracellular matrix production by cardiac fibroblasts in 3‐D cultures. PloS One 8: e79715, 2013.
 515. Tsuji T , Ishizaki T , Okamoto M , Higashida C , Kimura K , Furuyashiki T , Arakawa Y , Birge RB , Nakamoto T , Hirai H , Narumiya S . ROCK and mDia1 antagonize in Rho‐dependent Rac activation in Swiss 3T3 fibroblasts. J Cell Biol 157: 819‐830, 2002.
 516. Tsuruda T , Boerrigter G , Huntley BK , Noser JA , Cataliotti A , Costello‐Boerrigter LC , Chen HH , Burnett JC, Jr . Brain natriuretic Peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases. Circ Res 91: 1127‐1134, 2002.
 517. Tummalapalli CM , Heath BJ , Tyagi SC . Tissue inhibitor of metalloproteinase‐4 instigates apoptosis in transformed cardiac fibroblasts. J Cell Biochem 80: 512‐521, 2001.
 518. Turner CE . Paxillin interactions. J Cell Sci 113(Pt 23): 4139‐4140, 2000.
 519. Turner CE , Brown MC , Perrotta JA , Riedy MC , Nikolopoulos SN , McDonald AR , Bagrodia S , Thomas S , Leventhal PS . Paxillin LD4 motif binds PAK and PIX through a novel 95‐kD ankyrin repeat, ARF‐GAP protein: A role in cytoskeletal remodeling. J Cell Biol 145: 851‐863, 1999.
 520. Turner CE , Miller JT . Primary sequence of paxillin contains putative SH2 and SH3 domain binding motifs and multiple LIM domains: Identification of a vinculin and pp125Fak‐binding region. J Cell Sci 107(Pt 6): 1583‐1591, 1994.
 521. Tyagi SC , Campbell SE , Reddy HK , Tjahja E , Voelker DJ . Matrix metalloproteinase activity expression in infarcted, noninfarcted and dilated cardiomyopathic human hearts. Mol Cell Biochem 155: 13‐21, 1996.
 522. Tyagi SC , Kumar S , Glover G . Induction of tissue inhibitor and matrix metalloproteinase by serum in human heart‐derived fibroblast and endomyocardial endothelial cells. J Cell Biochem 58: 360‐371, 1995.
 523. Tyagi SC , Kumar SG , Banks J , Fortson W . Co‐expression of tissue inhibitor and matrix metalloproteinase in myocardium. J Mol Cell Cardiol 27: 2177‐2189, 1995.
 524. Ulmer TS , Calderwood DA , Ginsberg MH , Campbell ID . Domain‐specific interactions of talin with the membrane‐proximal region of the integrin beta3 subunit. Biochemistry 42: 8307‐8312, 2003.
 525. Valente AJ , Sakamuri SS , Siddesha JM , Yoshida T , Gardner JD , Prabhu R , Siebenlist U , Chandrasekar B . TRAF3IP2 mediates interleukin‐18‐induced cardiac fibroblast migration and differentiation. Cell Signal 25: 2176‐2184, 2013.
 526. Valente AJ , Yoshida T , Gardner JD , Somanna N , Delafontaine P , Chandrasekar B . Interleukin‐17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual‐specificity phosphatase MKP‐1/DUSP‐1. Cell Signal 24: 560‐568, 2012.
 527. Verrecchia F , Chu ML , Mauviel A . Identification of novel TGF‐beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 276: 17058‐17062, 2001.
 528. Verreck FA , de Boer T , Langenberg DM , Hoeve MA , Kramer M , Vaisberg E , Kastelein R , Kolk A , de Waal‐Malefyt R , Ottenhoff TH . Human IL‐23‐producing type 1 macrophages promote but IL‐10‐producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci U S A 101: 4560‐4565, 2004.
 529. Villar AV , Garcia R , Llano M , Cobo M , Merino D , Lantero A , Tramullas M , Hurle JM , Hurle MA , Nistal JF . BAMBI (BMP and activin membrane‐bound inhibitor) protects the murine heart from pressure‐overload biomechanical stress by restraining TGF‐beta signaling. Biochim Biophys Acta 1832: 323‐335, 2013.
 530. Visse R , Nagase H . Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res 92: 827‐839, 2003.
 531. Vivar R , Humeres C , Varela M , Ayala P , Guzman N , Olmedo I , Catalan M , Boza P , Munoz C , Diaz Araya G . Cardiac fibroblast death by ischemia/reperfusion is partially inhibited by IGF‐1 through both PI3K/Akt and MEK‐ERK pathways. Exp Mol Pathol 93: 1‐7, 2012.
 532. Vousden KH , Lane DP . p53 in health and disease. Nature Rev Mol Cell Biol 8: 275‐283, 2007.
 533. Vuori K , Hirai H , Aizawa S , Ruoslahti E . Introduction of p130cas signaling complex formation upon integrin‐mediated cell adhesion: A role for Src family kinases. Mol Cell Biol 16: 2606‐2613, 1996.
 534. Walker GA , Masters KS , Shah DN , Anseth KS , Leinwand LA . Valvular myofibroblast activation by transforming growth factor‐beta: Implications for pathological extracellular matrix remodeling in heart valve disease. Circ Res 95: 253‐260, 2004.
 535. Wang D , Chang PS , Wang Z , Sutherland L , Richardson JA , Small E , Krieg PA , Olson EN . Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105: 851‐862, 2001.
 536. Wang GL , Jiang BH , Rue EA , Semenza GL . Hypoxia‐inducible factor 1 is a basic‐helix‐loop‐helix‐PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92: 5510‐5514, 1995.
 537. Wang J , Zohar R , McCulloch CA . Multiple roles of alpha‐smooth muscle actin in mechanotransduction. Exp Cell Res 312: 205‐214, 2006.
 538. Wang LP , Wang Y , Zhao LM , Li GR , Deng XL . Angiotensin II upregulates K(Ca)3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts. Biochem Pharmacol 85: 1486‐1494, 2013.
 539. Wang P , Ballestrem C , Streuli CH . The C terminus of talin links integrins to cell cycle progression. J Cell Biol 195: 499‐513, 2011.
 540. Wang X , Khaidakov M , Ding Z , Dai Y , Mercanti F , Mehta JL . LOX‐1 in the maintenance of cytoskeleton and proliferation in senescent cardiac fibroblasts. J Mol Cell Cardiol 60: 184‐190, 2013.
 541. Wang X , Zhang L , Wei Z , Zhang X , Gao Q , Ma Y , Liu X , Jiang Y , Guo C . The inhibitory action of PDCD4 in lipopolysaccharide/D‐galactosamine‐induced acute liver injury. Lab Invest 93: 291‐302, 2013.
 542. Wang Y , Xu F , Chen J , Shen X , Deng Y , Xu L , Yin J , Chen H , Teng F , Liu X , Wu W , Jiang B , Guo DA . Matrix metalloproteinase‐9 induces cardiac fibroblast migration, collagen and cytokine secretion: Inhibition by salvianolic acid B from Salvia miltiorrhiza. Phytomedicine 19: 13‐19, 2011.
 543. Wang YS , Li SH , Guo J , Mihic A , Wu J , Sun L , Davis K , Weisel RD , Li RK . Role of miR‐145 in cardiac myofibroblast differentiation. J Mol Cell Cardiol 66: 94‐105, 2014.
 544. Watanabe N , Kato T , Fujita A , Ishizaki T , Narumiya S . Cooperation between mDia1 and ROCK in Rho‐induced actin reorganization. Nat Cell Biol 1: 136‐143, 1999.
 545. Webber J , Jenkins RH , Meran S , Phillips A , Steadman R . Modulation of TGFbeta1‐dependent myofibroblast differentiation by hyaluronan. Am J Pathol 175: 148‐160, 2009.
 546. Webber J , Meran S , Steadman R , Phillips A . Hyaluronan orchestrates transforming growth factor‐beta1‐dependent maintenance of myofibroblast phenotype. J Biol Chem 284: 9083‐9092, 2009.
 547. Weber KT . Monitoring tissue repair and fibrosis from a distance. Circulation 96: 2488‐2492, 1997.
 548. Weber KT , Brilla CG . Pathological hypertrophy and cardiac interstitium. Fibrosis and renin‐angiotensin‐aldosterone system. Circulation 83: 1849‐1865, 1991.
 549. Weber KT , Janicki JS , Pick R , Capasso J , Anversa P . Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am J Cardiol 65: 1G‐7G, 1990.
 550. Weber KT , Pick R , Jalil JE , Janicki JS , Carroll EP . Patterns of myocardial fibrosis. J Mol Cell Cardiol 21(Suppl 5): 121‐131, 1989.
 551. Wegener KL , Partridge AW , Han J , Pickford AR , Liddington RC , Ginsberg MH , Campbell ID . Structural basis of integrin activation by talin. Cell 128: 171‐182, 2007.
 552. Weidemann A , Johnson RS . Biology of HIF‐1alpha. Cell Death Differ 15: 621‐627, 2008.
 553. Weinberg RA . The retinoblastoma protein and cell cycle control. Cell 81: 323‐330, 1995.
 554. Wells RG , Discher DE . Matrix elasticity, cytoskeletal tension, and TGF‐beta: The insoluble and soluble meet. Sci Signal 1: pe13, 2008.
 555. 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.
 556. Wilson DP , Susnjar M , Kiss E , Sutherland C , Walsh MP . Thromboxane A2‐induced contraction of rat caudal arterial smooth muscle involves activation of Ca2+ entry and Ca2+ sensitization: Rho‐associated kinase‐mediated phosphorylation of MYPT1 at Thr‐855, but not Thr‐697. Biochem J 389: 763‐774, 2005.
 557. Wilson MA , Shukitt‐Hale B , Kalt W , Ingram DK , Joseph JA , Wolkow CA . Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 5: 59‐68, 2006.
 558. Wittmann T , Waterman‐Storer CM . Cell motility: Can Rho GTPases and microtubules point the way? J Cell Sci 114: 3795‐3803, 2001.
 559. Wong VW , Rustad KC , Akaishi S , Sorkin M , Glotzbach JP , Januszyk M , Nelson ER , Levi K , Paterno J , Vial IN , Kuang AA , Longaker MT , Gurtner GC . Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med 18: 148‐152, 2012.
 560. Worth DC , Hodivala‐Dilke K , Robinson SD , King SJ , Morton PE , Gertler FB , Humphries MJ , Parsons M . Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration. J Cell Biol 189: 369‐383, 2010.
 561. Wozniak MA , Cheng CQ , Shen CJ , Gao L , Olarerin‐George AO , Won KJ , Hogenesch JB , Chen CS . Adhesion regulates MAP kinase/ternary complex factor exchange to control a proliferative transcriptional switch. Curr Biol 22: 2017‐2026, 2012.
 562. Wozniak MA , Desai R , Solski PA , Der CJ , Keely PJ . ROCK‐generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three‐dimensional collagen matrix. J Cell Biol 163: 583‐595, 2003.
 563. Wrana JL . The secret life of Smad4. Cell 136: 13‐14, 2009.
 564. Wylie DE , Damsky CH , Buck CA . Studies on the function of cell surface glycoproteins. I. Use of antisera to surface membranes in the identification of membrane components relevant to cell‐substrate adhesion. J Cell Biol 80: 385‐402, 1979.
 565. Xu D , Kishi H , Kawamichi H , Kajiya K , Takada Y , Kobayashi S . Sphingosylphosphorylcholine induces stress fiber formation via activation of Fyn‐RhoA‐ROCK signaling pathway in fibroblasts. Cell Signal 24: 282‐289, 2012.
 566. Xuan Nguyen TL , Choi JW , Lee SB , Ye K , Woo SD , Lee KH , Ahn JY . Akt phosphorylation is essential for nuclear translocation and retention in NGF‐stimulated PC12 cells. Biochem Bioph Res Co 349: 789‐798, 2006.
 567. Yam CH , Fung TK , Poon RY . Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 59: 1317‐1326, 2002.
 568. Yamamoto T , Ebisuya M , Ashida F , Okamoto K , Yonehara S , Nishida E . Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell‐cycle progression. Curr Biol 16: 1171‐1182, 2006.
 569. Yang B , He K , Zheng F , Wan L , Yu X , Wang X , Zhao D , Bai Y , Chu W , Sun Y , Lu Y . Over‐expression of hypoxia‐inducible factor‐1 alpha in vitro protects the cardiac fibroblasts from hypoxia‐induced apoptosis. J Cardiovasc Med (Hagerstown) 15: 579‐586, 2014.
 570. Yang F , Chung AC , Huang XR , Lan HY . Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor‐beta‐dependent and ‐independent Smad pathways: The role of Smad3. Hypertension 54: 877‐884, 2009.
 571. Yang F , Zhu XL , Wang LP , Song XD , Wang RM , Li ZG , Luo L , Hu WM , Ma WD , Pei X , Zhang LJ , Li QJ . Role of AcSDKP on collagen synthesis and degradation in cultured rat cardiac fibroblast. Zhonghua Xin Xue Guan Bing Za Zhi 34: 843‐846, 2006.
 572. Ye F , Hu G , Taylor D , Ratnikov B , Bobkov AA , McLean MA , Sligar SG , Taylor KA , Ginsberg MH . Recreation of the terminal events in physiological integrin activation. J Cell Biol 188: 157‐173, 2010.
 573. Ye N , Verma D , Meng F , Davidson MW , Suffoletto K , Hua SZ . Direct observation of alpha‐actinin tension and recruitment at focal adhesions during contact growth. Exp Cell Res 327: 57‐67, 2014.
 574. Yi X , Li X , Zhou Y , Ren S , Wan W , Feng G , Jiang X . Hepatocyte growth factor regulates the TGF‐beta1‐induced proliferation, differentiation and secretory function of cardiac fibroblasts. Int J Mol Med 34: 381‐390, 2014.
 575. Yonemura S , Wada Y , Watanabe T , Nagafuchi A , Shibata M . alpha‐Catenin as a tension transducer that induces adherens junction development. Nat Cell Biol 12: 533‐542, 2010.
 576. 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.
 577. Yu Q , Stamenkovic I . Cell surface‐localized matrix metalloproteinase‐9 proteolytically activates TGF‐beta and promotes tumor invasion and angiogenesis. Genes Dev 14: 163‐176, 2000.
 578. Yue L , Xie J , Nattel S . Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res 89: 744‐753, 2011.
 579. Yue Z , Zhang Y , Xie J , Jiang J , Yue L . Transient receptor potential (TRP) channels and cardiac fibrosis. Curr Top Med Chem 13: 270‐282, 2013.
 580. Zaidel‐Bar R , Ballestrem C , Kam Z , Geiger B . Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J Cell Sci 116: 4605‐4613, 2003.
 581. Zamilpa R , Lopez EF , Chiao YA , Dai Q , Escobar GP , Hakala K , Weintraub ST , Lindsey ML . Proteomic analysis identifies in vivo candidate matrix metalloproteinase‐9 substrates in the left ventricle post‐myocardial infarction. Proteomics 10: 2214‐2223, 2010.
 582. 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.
 583. Zhang G , Moorhead PJ , el Nahas AM . Myofibroblasts and the progression of experimental glomerulonephritis. Exp Nephrol 3: 308‐318, 1995.
 584. Zhang HY , Gharaee‐Kermani M , Zhang K , Karmiol S , Phan SH . Lung fibroblast alpha‐smooth muscle actin expression and contractile phenotype in bleomycin‐induced pulmonary fibrosis. Am J Pathol 148: 527‐537, 1996.
 585. Zhang X , Chattopadhyay A , Ji QS , Owen JD , Ruest PJ , Carpenter G , Hanks SK . Focal adhesion kinase promotes phospholipase C‐gamma1 activity. Proc Natl Acad Sci U S A 96: 9021‐9026, 1999.
 586. Zhang X , Jiang G , Cai Y , Monkley SJ , Critchley DR , Sheetz MP . Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nat Cell Biol 10: 1062‐1068, 2008.
 587. Zhang X , Moore SW , Iskratsch T , Sheetz MP . N‐WASP‐directed actin polymerization activates Cas phosphorylation and lamellipodium spreading. J Cell Sci 127: 1394‐1405, 2014.
 588. Zhao XH , Laschinger C , Arora P , Szaszi K , Kapus A , McCulloch CA . Force activates smooth muscle alpha‐actin promoter activity through the Rho signaling pathway. J Cell Sci 120: 1801‐1809, 2007.
 589. Zhao ZS , Manser E , Loo TH , Lim L . Coupling of PAK‐interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol Cell Biol 20: 6354‐6363, 2000.
 590. Zhu F , Li Y , Zhang J , Piao C , Liu T , Li HH , Du J . Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PloS One 8: e74535, 2013.
 591. Ziegler WH , Liddington RC , Critchley DR . The structure and regulation of vinculin. Trends Cell Biol 16: 453‐460, 2006.
 592. Zimmermann J , Brunner C , Enculescu M , Goegler M , Ehrlicher A , Kas J , Falcke M . Actin filament elasticity and retrograde flow shape the force‐velocity relation of motile cells. Biophys J 102: 287‐295, 2012.
 593. Zou Y , Komuro I , Yamazaki T , Kudoh S , Aikawa R , Zhu W , Shiojima I , Hiroi Y , Tobe K , Kadowaki T , Yazaki Y . Cell type‐specific angiotensin II‐evoked signal transduction pathways: Critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res 82: 337‐345, 1998.

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Article Title: Intracellular Signaling of Cardiac Fibroblasts
 

How to Cite

Patricia L. Roche, Krista L. Filomeno, Rushita A. Bagchi, Michael P. Czubryt. Intracellular Signaling of Cardiac Fibroblasts. Compr Physiol 2015, 5: 721-760. doi: 10.1002/cphy.c140044