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Modulation of Systemic Metabolism by MMP‐2: From MMP‐2 Deficiency in Mice to MMP‐2 Deficiency in Patients

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ABSTRACT

Matrix metalloproteinase‐2 (MMP‐2) is a 72‐kDa zinc‐ and calcium‐dependent endopeptidase with intracellular and extracellular functions ranging from the modulation of extracellular matrix remodeling to cell growth and migration, angiogenesis, inflammation, and metabolism. An upregulation of MMP‐2 activity has the potential to deregulate lipid metabolism through the cleavage of numerous metabolic mediators including plasma lipoproteins and cell surface receptors of lipoproteins. Paradoxically, MMP‐2 deficiency induces inflammation and deregulates metabolism. Humans and mice with a deficiency in MMP‐2 activity share a complex metabolic and inflammatory syndrome including cardiac dysfunction associated with congenital heart defects (in humans) and metabolic disorder (mice), arthritis, loss of bone mass, lipodystrophy, and delayed growth. The etiology of the inflammatory and metabolic syndrome in MMP‐2 deficiency is unknown and there is currently no cure for MMP‐2 deficiency in patients. Recent research suggests that the pathophysiology of MMP‐2 deficiency in mice and humans is influenced by a heart‐centric endocrine mechanism signaled by a cardiac‐specific secreted phospholipase A2 (cardiac sPLA2), which is released from cardiomyocytes in response to monocyte chemoattractant protein‐3, a proinflammatory cytokine normally cleaved and inactivated by MMP‐2. This review summarizes many important proteolytic functions of MMP‐2 and recapitulates recent reports linking the heart to systemic metabolic control through the MMP‐2/cardiac sPLA2 axis. The authors suggest that MMP‐2 deficiency should, perhaps, be viewed and treated as an endocrine condition of excess sPLA2, a concept with particular importance for the therapeutic treatment of MMP‐2‐deficient patients. The possible existence of tissue‐specific MMP/cytokine/PLA2 signaling systems is discussed. © 2016 American Physiological Society. Compr Physiol 6:1935‐1949, 2016.

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Figure 1. Figure 1. Members of the MMP family share a largely conserved domain structure ().
Figure 2. Figure 2. (A) Linear structure and domain organization of MMP‐2. (B) The catalytic activity of MMP‐2 (72 kDa) is strongly regulated by its propeptide domain (). A cysteine residue within the propeptide domain binds to the Zn2+ atom in the catalytic domain inhibiting substrate binding and proteolysis. Oxidative stress and proteolysis are two mechanisms of MMP‐2 activation. S‐gluthathiolation is induced by oxidative stress. Purportedly, peroxynitrite (ONOO) reacts with celullar GSH and a critical cysteine residue in the conserved region (PRCGVPD) of the propeptide domain. The S‐gluthathiolated cysteine no longer can complex with the Zn2+ atom in the catalytic domain. The resultant enzyme (72 kDa) is active despite containing the propeptide domain. Proteolytic removal of the propeptide domain [e.g., by MMP‐14, and coagulation cascade proteases such as thrombin () and plasmin ()] is a major mechanism yielding catalytically active MMP‐2 (64 kDa).
Figure 3. Figure 3. Endocrine model of metabolic and inflammatory syndrome in MMP‐2 deficiency. (A) In normal physiology, MMP‐2 is anti‐inflammatory by cleaving and inactivating proinflammatory cytokines, such as monocyte chemoattractant protein‐3 (MCP‐3) (). MMP‐2 deficiency results in an excess of cardiac MCP‐3, which promotes the release of active cardiac sPLA2 from myocardium (). The release of cardiac sPLA2 from myocardium is governed by MMP‐2 and may enable the heart to exert important endocrine functions such as regulation of metabolism and inflammation in target organs including the heart, liver, adipose tissue bones, and skeletal muscle. (B) MMP‐2 deficiency causes similar problems in humans and mice, which could be explained as an excess of cardiac sPLA2. (C) The proinflammatory activity of cardiac sPLA2 is kept in balance by the anti‐inflammatory activity of MMP‐2, which prevents cardiac sPLA2 release from myocardium. Studies with mice suggest that MMP‐2 gene mutations and polymorphisms as well as drugs with MMP inhibitory actions may inhibit MMP‐2 catalytic activity inducing a state of MMP‐2 deficiency where inflammation is promoted, at least in part, by the relative excess of cardiac sPLA2 activity versus MMP‐2 activity (). It is thus suggested that treatment of metabolic and inflammatory syndrome in MMP‐2‐deficient patients should be directed to inhibiting sPLA2 activity. An alternative would be gene editing to correct the MMP‐2 gene defect in patients such that MMP‐2 activity (and consequently, cardiac sPLA2 activity) are restored to normal levels.
Figure 4. Figure 4. Proposed heart‐centric endocrine metabolic circuits mediated by cardiac secreted PLA2 and governed by MMP‐2. The heart is thought to be a major source of cardiac sPLA2, whose release is stimulated by MCP‐3, a chemokine normally cleaved and converted into a chemokine receptor antagonist by MMP‐2. Cardiac sPLA2 circulates in the plasma and may thus reach distant target organs affecting their inflammatory and lipid metabolic phenotype. An endocrine function of the heart is to release cardiac sPLA2, which signals to the liver to provide the heart with triglycerides in the form of VLDL. Other factors released from noncardiac target organs (indicated by “?” in the diagram) could also influence the metabolism of the heart.


Figure 1. Members of the MMP family share a largely conserved domain structure ().


Figure 2. (A) Linear structure and domain organization of MMP‐2. (B) The catalytic activity of MMP‐2 (72 kDa) is strongly regulated by its propeptide domain (). A cysteine residue within the propeptide domain binds to the Zn2+ atom in the catalytic domain inhibiting substrate binding and proteolysis. Oxidative stress and proteolysis are two mechanisms of MMP‐2 activation. S‐gluthathiolation is induced by oxidative stress. Purportedly, peroxynitrite (ONOO) reacts with celullar GSH and a critical cysteine residue in the conserved region (PRCGVPD) of the propeptide domain. The S‐gluthathiolated cysteine no longer can complex with the Zn2+ atom in the catalytic domain. The resultant enzyme (72 kDa) is active despite containing the propeptide domain. Proteolytic removal of the propeptide domain [e.g., by MMP‐14, and coagulation cascade proteases such as thrombin () and plasmin ()] is a major mechanism yielding catalytically active MMP‐2 (64 kDa).


Figure 3. Endocrine model of metabolic and inflammatory syndrome in MMP‐2 deficiency. (A) In normal physiology, MMP‐2 is anti‐inflammatory by cleaving and inactivating proinflammatory cytokines, such as monocyte chemoattractant protein‐3 (MCP‐3) (). MMP‐2 deficiency results in an excess of cardiac MCP‐3, which promotes the release of active cardiac sPLA2 from myocardium (). The release of cardiac sPLA2 from myocardium is governed by MMP‐2 and may enable the heart to exert important endocrine functions such as regulation of metabolism and inflammation in target organs including the heart, liver, adipose tissue bones, and skeletal muscle. (B) MMP‐2 deficiency causes similar problems in humans and mice, which could be explained as an excess of cardiac sPLA2. (C) The proinflammatory activity of cardiac sPLA2 is kept in balance by the anti‐inflammatory activity of MMP‐2, which prevents cardiac sPLA2 release from myocardium. Studies with mice suggest that MMP‐2 gene mutations and polymorphisms as well as drugs with MMP inhibitory actions may inhibit MMP‐2 catalytic activity inducing a state of MMP‐2 deficiency where inflammation is promoted, at least in part, by the relative excess of cardiac sPLA2 activity versus MMP‐2 activity (). It is thus suggested that treatment of metabolic and inflammatory syndrome in MMP‐2‐deficient patients should be directed to inhibiting sPLA2 activity. An alternative would be gene editing to correct the MMP‐2 gene defect in patients such that MMP‐2 activity (and consequently, cardiac sPLA2 activity) are restored to normal levels.


Figure 4. Proposed heart‐centric endocrine metabolic circuits mediated by cardiac secreted PLA2 and governed by MMP‐2. The heart is thought to be a major source of cardiac sPLA2, whose release is stimulated by MCP‐3, a chemokine normally cleaved and converted into a chemokine receptor antagonist by MMP‐2. Cardiac sPLA2 circulates in the plasma and may thus reach distant target organs affecting their inflammatory and lipid metabolic phenotype. An endocrine function of the heart is to release cardiac sPLA2, which signals to the liver to provide the heart with triglycerides in the form of VLDL. Other factors released from noncardiac target organs (indicated by “?” in the diagram) could also influence the metabolism of the heart.
References
 1.Abd‐Allah SH, El‐Shal AS, Shalaby SM, Pasha HF, Abou El‐Saoud AM, Abdel Galil SM, Mahmoud TA. Influence of Matrix metalloproteinase 1 and 3 genetic variations on susceptibility and severity of juvenile idiopathic arthritis. IUBMB Life 67: 934‐942, 2015.
 2.Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34: 154‐156, 2003.
 3.Ali MA, Fan X, Schulz R. Cardiac sarcomeric proteins: Novel intracellular targets of matrix metalloproteinase‐2 in heart disease. Trends Cardiovasc Med 21: 112‐118, 2011.
 4.Andoh A, Takaya H, Saotome T, Shimada M, Hata K, Araki Y, Nakamura F, Shintani Y, Fujiyama Y, Bamba T. Cytokine regulation of chemokine (IL‐8, MCP‐1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology 119: 211‐219, 2000.
 5.Aoki T, Sato D, Li Y, Takino T, Miyamori H, Sato H. Cleavage of apolipoprotein E by membrane‐type matrix metalloproteinase‐1 abrogates suppression of cell proliferation. J Biochem 137: 95‐99, 2005.
 6.Baramova EN, Bajou K, Remacle A, L'Hoir C, Krell HW, Weidle UH, Noel A, Foidart JM. Involvement of PA/plasmin system in the processing of pro‐MMP‐9 and in the second step of pro‐MMP‐2 activation. FEBS Lett 405: 157‐162, 1997.
 7.Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of peroxisome proliferator‐activated receptor‐alpha during cardiac hypertrophic growth. J Clin Invest 105: 1723‐1730, 2000.
 8.Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10: 238‐245, 2000.
 9.Baricos WH, Cortez SL, el‐Dahr SS, Schnaper HW. ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP‐2 cascade. Kidney Int 47: 1039‐1047, 1995.
 10.Barlaka E, Galatou E, Mellidis K, Ravingerova T, Lazou A. Role of pleiotropic properties of peroxisome proliferator‐activated receptors in the heart: Focus on the nonmetabolic effects in cardiac protection. Cardiovasc Ther 34: 37‐48, 2016.
 11.Barlaka E, Gorbe A, Gaspar R, Paloczi J, Ferdinandy P, Lazou A. Activation of PPARbeta/delta protects cardiac myocytes from oxidative stress‐induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases. Pharmacol Res 95‐96: 102‐110, 2015.
 12.Bauters D, Van Hul M, Lijnen HR. Gelatinase B (MMP‐9) gene silencing does not affect murine preadipocyte differentiation. Adipocyte 3: 50‐53, 2014.
 13.Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK. The LDL‐receptor‐related protein, LRP, is an apolipoprotein E‐binding protein. Nature 341: 162‐164, 1989.
 14.Belkin AM, Zemskov EA, Hang J, Akimov SS, Sikora S, Strongin AY. Cell‐surface‐associated tissue transglutaminase is a target of MMP‐2 proteolysis. Biochemistry 43: 11760‐11769, 2004.
 15.Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG. NARC‐1/PCSK9 and its natural mutants: Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279: 48865‐48875, 2004.
 16.Berry E, Bosonea AM, Wang X, Fernandez‐Patron C. Insights into the activity, differential expression, mutual regulation, and functions of matrix metalloproteinases and a disintegrin and metalloproteinases in hypertension and cardiac disease. J Vasc Res 50: 52‐68, 2013.
 17.Berry E, Hernandez‐Anzaldo S, Ghomashchi F, Lehner R, Murakami M, Gelb MH, Kassiri Z, Wang X, Fernandez‐Patron C. Matrix metalloproteinase‐2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever. J Am Heart Assoc 4: pii: e001868, 2015.
 18.Berton A, Rigot V, Huet E, Decarme M, Eeckhout Y, Patthy L, Godeau G, Hornebeck W, Bellon G, Emonard H. Involvement of fibronectin type II repeats in the efficient inhibition of gelatinases A and B by long‐chain unsaturated fatty acids. J Biol Chem 276: 20458‐20465, 2001.
 19.Bode W, Fernandez‐Catalan C, Tschesche H, Grams F, Nagase H, Maskos K. Structural properties of matrix metalloproteinases. Cell Mol Life Sci 55: 639‐652, 1999.
 20.Brown MS, Goldstein JL. Koch's postulates for cholesterol. Cell 71: 187‐188, 1992.
 21.Carnevale KA, Cathcart MK. Calcium‐independent phospholipase A(2) is required for human monocyte chemotaxis to monocyte chemoattractant protein 1. J Immunol 167: 3414‐3421, 2001.
 22.Castberg FC, Kjaergaard S, Mosig RA, Lobl M, Martignetti C, Martignetti JA, Myrup C, Zak M. Multicentric osteolysis with nodulosis and arthropathy (MONA) with cardiac malformation, mimicking polyarticular juvenile idiopathic arthritis: Case report and literature review. Eur J Pediatr 172: 1657‐1663, 2013.
 23.Cauwe B, Opdenakker G. Intracellular substrate cleavage: A novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases. Crit Rev Biochem Mol Biol 45: 351‐423, 2010.
 24.Chakraborti S, Chowdhury A, Alam MN, Sarkar J, Mandal A, Pramanik A, Chakraborti T. Vascular aneurysms: A perspective. Indian J Biochem Biophys 51: 449‐456, 2014.
 25.Chernov AV, Sounni NE, Remacle AG, Strongin AY. Epigenetic control of the invasion‐promoting MT1‐MMP/MMP‐2/TIMP‐2 axis in cancer cells. J Biol Chem 284: 12727‐12734, 2009.
 26.Cheung C, Marchant D, Walker EK, Luo Z, Zhang J, Yanagawa B, Rahmani M, Cox J, Overall C, Senior RM, Luo H, McManus BM. Ablation of matrix metalloproteinase‐9 increases severity of viral myocarditis in mice. Circulation 117: 1574‐1582, 2008.
 27.Choi YA, Kim DK, Bang OS, Kang SS, Jin EJ. Secretory phospholipase A2 promotes MMP‐9‐mediated cell death by degrading type I collagen via the ERK pathway at an early stage of chondrogenesis. Biol Cell 102: 107‐119, 2010.
 28.Choi YA, Lim HK, Kim JR, Lee CH, Kim YJ, Kang SS, Baek SH. Group IB secretory phospholipase A2 promotes matrix metalloproteinase‐2‐mediated cell migration via the phosphatidylinositol 3‐kinase and Akt pathway. J Biol Chem 279: 36579‐36585, 2004.
 29.Chow AK, Cena J, El‐Yazbi AF, Crawford BD, Holt A, Cho WJ, Daniel EE, Schulz R. Caveolin‐1 inhibits matrix metalloproteinase‐2 activity in the heart. J Mol Cell Cardiol 42: 896‐901, 2007.
 30.Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol 152: 189‐205, 2007.
 31.Corry DB, Kiss A, Song LZ, Song L, Xu J, Lee SH, Werb Z, Kheradmand F. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J 18: 995‐997, 2004.
 32.Corry DB, Rishi K, Kanellis J, Kiss A, Song Lz LZ, Xu J, Feng L, Werb Z, Kheradmand F. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2‐deficiency. Nat Immunol 3: 347‐353, 2002.
 33.de Rooy DP, Zhernakova A, Tsonaka R, Willemze A, Kurreeman BA, Trynka G, van Toorn L, Toes RE, Huizinga TW, Houwing‐Duistermaat JJ, Gregersen PK, van der Helm‐van Mil AH. A genetic variant in the region of MMP‐9 is associated with serum levels and progression of joint damage in rheumatoid arthritis. Ann Rheum Dis 73: 1163‐1169, 2014.
 34.DeCoux A, Lindsey ML, Villarreal F, Garcia RA, Schulz R. Myocardial matrix metalloproteinase‐2: Inside out and upside down. J Mol Cell Cardiol 77: 64‐72, 2014.
 35.Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Phospholipase A2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111: 6130‐6185, 2011.
 36.Deryugina EI, Ratnikov B, Monosov E, Postnova TI, DiScipio R, Smith JW, Strongin AY. MT1‐MMP initiates activation of pro‐MMP‐2 and integrin alphavbeta3 promotes maturation of MMP‐2 in breast carcinoma cells. Exp Cell Res 263: 209‐223, 2001.
 37.Dollery CM, Libby P. Atherosclerosis and proteinase activation. Cardiovasc Res 69: 625‐635, 2006.
 38.Doucet A, Overall CM. Protease proteomics: revealing protease in vivo functions using systems biology approaches. Mol Aspects Med 29: 339‐358, 2008.
 39.Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 365: 1415‐1428, 2005.
 40.Emonard H, Bellon G, de Diesbach P, Mettlen M, Hornebeck W, Courtoy PJ. Regulation of matrix metalloproteinase (MMP) activity by the low‐density lipoprotein receptor‐related protein (LRP). A new function for an “old friend”. Biochimie 87: 369‐376, 2005.
 41.Fernandez‐Patron C, Leung D. Emergence of a metalloproteinase/phospholipase A2 axis of systemic inflammation. Metalloproteinases Med 2: 29‐38, 2015.
 42.Fernandez‐Patron C, Zhang Y, Radomski MW, Hollenberg MD, Davidge ST. Rapid release of matrix metalloproteinase (MMP)‐2 by thrombin in the rat aorta: Modulation by protein tyrosine kinase/phosphatase. Thromb Haemost 82: 1353‐1357, 1999.
 43.Fromigue O, Hamidouche Z, Marie PJ. Blockade of the RhoA‐JNK‐c‐Jun‐MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem 283: 30549‐30556, 2008.
 44.Fukumoto Y, Libby P, Rabkin E, Hill CC, Enomoto M, Hirouchi Y, Shiomi M, Aikawa M. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits. Circulation 103: 993‐999, 2001.
 45.Galis ZS, Asanuma K, Godin D, Meng X. N‐acetyl‐cysteine decreases the matrix‐degrading capacity of macrophage‐derived foam cells: New target for antioxidant therapy? Circulation 97: 2445‐2453, 1998.
 46.Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94: 2493‐2503, 1994.
 47.Galvez BG, Matias‐Roman S, Yanez‐Mo M, Vicente‐Manzanares M, Sanchez‐Madrid F, Arroyo AG. Caveolae are a novel pathway for membrane‐type 1 matrix metalloproteinase traffic in human endothelial cells. Mol Biol Cell 15: 678‐687, 2004.
 48.Gasparovic I, Cizmarevic NS, Lovrecic L, Perkovic O, Lavtar P, Sepcic J, Jazbec SS, Kapovic M, Peterlin B, Ristic S. MMP‐2‐1575G/A polymorphism modifies the onset of optic neuritis as a first presenting symptom in MS? J Neuroimmunol 286: 13‐15, 2015.
 49.Gorovetz M, Schwob O, Krimsky M, Yedgar S, Reich R. MMP production in human fibrosarcoma cells and their invasiveness are regulated by group IB secretory phospholipase A2 receptor‐mediated activation of cytosolic phospholipase A2. Front Biosci 13: 1917‐1925, 2008.
 50.Greenlee KJ, Werb Z, Kheradmand F. Matrix metalloproteinases in lung: Multiple, multifarious, and multifaceted. Physiol Rev 87: 69‐98, 2007.
 51.Gross J, Nagai Y. Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc Natl Acad Sci U S A 54: 1197‐1204, 1965.
 52.Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 89: 2595‐2600, 2004.
 53.Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 26: 364‐373, 2015.
 54.Han KH, Hong KH, Park JH, Ko J, Kang DH, Choi KJ, Hong MK, Park SW, Park SJ. C‐reactive protein promotes monocyte chemoattractant protein‐1–mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes. Circulation 109: 2566‐2571, 2004.
 55.Hartl D, Krauss‐Etschmann S, Koller B, Hordijk PL, Kuijpers TW, Hoffmann F, Hector A, Eber E, Marcos V, Bittmann I, Eickelberg O, Griese M, Roos D. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J Immunol 181: 8053‐8067, 2008.
 56.Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka‐Yoshida K, Itoh T, Takeshita A. Targeted deletion of MMP‐2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol 285: H1229‐H1235, 2003.
 57.Hernandez‐Anzaldo S, Berry E, Brglez V, Leung D, Yun TJ, Lee JS, Filep JG, Kassiri Z, Cheong C, Lambeau G, Lehner R, Fernandez‐Patron C. Identification of a novel heart‐liver axis: Matrix metalloproteinase‐2 negatively regulates cardiac secreted phospholipase A2 to modulate lipid metabolism and inflammation in the liver. J Am Heart Assoc 4(11). pii: e002553, 2015.
 58.Hooper NM. Families of zinc metalloproteases. FEBS Lett 354: 1‐6, 1994.
 59.Hori Y, Kunihiro S, Sato S, Yoshioka K, Hara Y, Kanai K, Hoshi F, Itoh N, Higuchi S. Doxycycline attenuates isoproterenol‐induced myocardial fibrosis and matrix metalloproteinase activity in rats. Biol Pharm Bull 32: 1678‐1682, 2009.
 60.Horton JD, Cohen JC, Hobbs HH. PCSK9: A convertase that coordinates LDL catabolism. J Lipid Res 50(Suppl): S172‐S177, 2009.
 61.Hughes BG, Schulz R. Targeting MMP‐2 to treat ischemic heart injury. Basic Res Cardiol 109: 424, 2014.
 62.Ii H, Hontani N, Toshida I, Oka M, Sato T, Akiba S. Group IVA phospholipase A2‐associated production of MMP‐9 in macrophages and formation of atherosclerotic lesions. Biol Pharm Bull 31: 363‐368, 2008.
 63.Ito Y, Kaneko N, Iwasaki T, Morikawa S, Kaneko K, Masumoto J. IL‐1 as a target in inflammation. Endocr Metab Immune Disord Drug Targets 15: 206‐211, 2015.
 64.Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix metalloproteinase‐2 and matrix metalloproteinase‐9 in antibody‐induced arthritis. J Immunol 169: 2643‐2647, 2002.
 65.Iyer RP, de Castro Bras LE, Jin YF, Lindsey ML. Translating Koch's postulates to identify matrix metalloproteinase roles in postmyocardial infarction remodeling: Cardiac metalloproteinase actions (CarMA) postulates. Circ Res 114: 860‐871, 2014.
 66.Jackson CL, Raines EW, Ross R, Reidy MA. Role of endogenous platelet‐derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb 13: 1218‐1226, 1993.
 67.Jahng JW, Song E, Sweeney G. Crosstalk between the heart and peripheral organs in heart failure. Exp Mol Med 48: e217, 2016.
 68.Jaworski DM, Sideleva O, Stradecki HM, Langlois GD, Habibovic A, Satish B, Tharp WG, Lausier J, Larock K, Jetton TL, Peshavaria M, Pratley RE. Sexually dimorphic diet‐induced insulin resistance in obese tissue inhibitor of metalloproteinase‐2 (TIMP‐2)‐deficient mice. Endocrinology 152: 1300‐1313, 2011.
 69.Jung HO, Uhm JS, Seo SM, Kim JH, Youn HJ, Baek SH, Chung WS, Seung KB. Angiotensin II‐induced smooth muscle cell migration is mediated by LDL receptor‐related protein 1 via regulation of matrix metalloproteinase 2 expression. Biochem Biophys Res Commun 402: 577‐582, 2010.
 70.Kalaany NY, Mangelsdorf DJ. LXRS and FXR: The yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68: 159‐191, 2006.
 71.Kang S, Kim ES, Moon A. Simvastatin and lovastatin inhibit breast cell invasion induced by H‐Ras. Oncol Rep 21: 1317‐1322, 2009.
 72.Kapoor C, Vaidya S, Wadhwan V, Kaur G, Pathak A. Seesaw of matrix metalloproteinases (MMPs). J Cancer Res Ther 12: 28‐35, 2016.
 73.Kim JK, Mun S, Kim MS, Kim MB, Sa BK, Hwang JK. 5,7‐Dimethoxyflavone, an activator of PPARalpha/gamma, inhibits UVB‐induced MMP expression in human skin fibroblast cells. Exp Dermatol 21: 211‐216, 2012.
 74.Kim KH, Cho YS, Park JM, Yoon SO, Kim KW, Chung AS. Pro‐MMP‐2 activation by the PPARgamma agonist, ciglitazone, induces cell invasion through the generation of ROS and the activation of ERK. FEBS Lett 581: 3303‐3310, 2007.
 75.Kim SY, Park SM, Lee ST. Apolipoprotein C‐II is a novel substrate for matrix metalloproteinases. Biochem Biophys Res Commun 339: 47‐54, 2006.
 76.Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res 51: 85‐94, 2005.
 77.Kristensen T, Moestrup SK, Gliemann J, Bendtsen L, Sand O, Sottrup‐Jensen L. Evidence that the newly cloned low‐density‐lipoprotein receptor related protein (LRP) is the alpha 2‐macroglobulin receptor. FEBS Lett 276: 151‐155, 1990.
 78.Kumari S, Mg S, Mayor S. Endocytosis unplugged: multiple ways to enter the cell. Cell Res 20: 256‐275, 2010.
 79.Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem 77: 495‐520, 2008.
 80.Lee JM, Choudhury RP. Prospects for atherosclerosis regression through increase in high‐density lipoprotein and other emerging therapeutic targets. Heart 93: 559‐564, 2007.
 81.Lee SW, Song KE, Shin DS, Ahn SM, Ha ES, Kim DJ, Nam MS, Lee KW. Alterations in peripheral blood levels of TIMP‐1, MMP‐2, and MMP‐9 in patients with type‐2 diabetes. Diabetes Res Clin Pract 69: 175‐179, 2005.
 82.Li P, Tao SS, Zhao MQ, Li J, Wang X, Pan HF, Ye DQ. Association study of matrix metalloproteinases gene polymorphisms with susceptibility to rheumatoid arthritis: A meta‐analysis. Immunol Invest 44: 603‐615, 2015.
 83.Lijnen HR, Collen D. Matrix metalloproteinase system deficiencies and matrix degradation. Thromb Haemost 82: 837‐845, 1999.
 84.Lijnen HR, Demeulemeester D, Van Hoef B, Collen D, Maquoi E. Deficiency of tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1) impairs nutritionally induced obesity in mice. Thromb Haemost 89: 249‐255, 2003.
 85.Lijnen HR, Silence J, Lemmens G, Frederix L, Collen D. Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. Thromb Haemost 79: 1171‐1176, 1998.
 86.Lillis AP, Van Duyn LB, Murphy‐Ullrich JE, Strickland DK. LDL receptor‐related protein 1: Unique tissue‐specific functions revealed by selective gene knockout studies. Physiol Rev 88: 887‐918, 2008.
 87.Liu Q, Zhang J, Tran H, Verbeek MM, Reiss K, Estus S, Bu G. LRP1 shedding in human brain: Roles of ADAM10 and ADAM17. Mol Neurodegener 4: 17, 2009.
 88.Lohi J, Wilson CL, Roby JD, Parks WC. Epilysin, a novel human matrix metalloproteinase (MMP‐28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 276: 10134‐10144, 2001.
 89.Lopez‐Otin C, Overall CM. Protease degradomics: A new challenge for proteomics. Nat Rev Mol Cell Biol 3: 509‐519, 2002.
 90.Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS. A novel intracellular isoform of matrix metalloproteinase‐2 induced by oxidative stress activates innate immunity. PLoS One 7: e34177, 2012.
 91.Lovett DH, Mahimkar R, Raffai RL, Cape L, Zhu BQ, Jin ZQ, Baker AJ, Karliner JS. N‐terminal truncated intracellular matrix metalloproteinase‐2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure. PLoS One 8: e68154, 2013.
 92.Luan Z, Chase AJ, Newby AC. Statins inhibit secretion of metalloproteinases‐1, ‐2, ‐3, and ‐9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol 23: 769‐775, 2003.
 93.Mahley RW, Innerarity TL, Rall SC, Jr., Weisgraber KH. Plasma lipoproteins: Apolipoprotein structure and function. J Lipid Res 25: 1277‐1294, 1984.
 94.Marcel YL, Kiss RS. Structure‐function relationships of apolipoprotein A‐I: A flexible protein with dynamic lipid associations. Curr Opin Lipidol 14: 151‐157, 2003.
 95.Marcoff L, Thompson PD. The role of coenzyme Q10 in statin‐associated myopathy: A systematic review. J Am Coll Cardiol 49: 2231‐2237, 2007.
 96.Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28: 261‐265, 2001.
 97.Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator‐activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 83: 1097‐1103, 1998.
 98.Marx N, Sukhova G, Murphy C, Libby P, Plutzky J. Macrophages in human atheroma contain PPARgamma: Differentiation‐dependent peroxisomal proliferator‐activated receptor gamma(PPARgamma) expression and reduction of MMP‐9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol 153: 17‐23, 1998.
 99.Matsumura S, Iwanaga S, Mochizuki S, Okamoto H, Ogawa S, Okada Y. Targeted deletion or pharmacological inhibition of MMP‐2 prevents cardiac rupture after myocardial infarction in mice. J Clin Invest 115: 599‐609, 2005.
 100.Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47: 711‐717, 2006.
 101.Matsusaka H, Ikeuchi M, Matsushima S, Ide T, Kubota T, Feldman AM, Takeshita A, Sunagawa K, Tsutsui H. Selective disruption of MMP‐2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine‐induced cardiomyopathy. Am J Physiol Heart Circ Physiol 289: H1858‐H1864, 2005.
 102.McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark‐Lewis I, Overall CM. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein‐3. Science 289: 1202‐1206, 2000.
 103.McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark‐Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti‐inflammatory properties in vivo. Blood 100: 1160‐1167, 2002.
 104.Mishra RS, Carnevale KA, Cathcart MK. iPLA2beta: Front and center in human monocyte chemotaxis to MCP‐1. J Exp Med 205: 347‐359, 2008.
 105.Moestrup SK, Gliemann J, Pallesen G. Distribution of the alpha 2‐macroglobulin receptor/low density lipoprotein receptor‐related protein in human tissues. Cell Tissue Res 269: 375‐382, 1992.
 106.Moestrup SK, Verroust PJ. Megalin‐ and cubilin‐mediated endocytosis of protein‐bound vitamins, lipids, and hormones in polarized epithelia. Annu Rev Nutr 21: 407‐428, 2001.
 107.Monden Y, Kubota T, Inoue T, Tsutsumi T, Kawano S, Ide T, Tsutsui H, Sunagawa K. Tumor necrosis factor‐alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am J Physiol Heart Circ Physiol 293: H743‐H753, 2007.
 108.Monea S, Lehti K, Keski‐Oja J, Mignatti P. Plasmin activates pro‐matrix metalloproteinase‐2 with a membrane‐type 1 matrix metalloproteinase‐dependent mechanism. J Cell Physiol 192: 160‐170, 2002.
 109.Morrison CJ, Butler GS, Rodriguez D, Overall CM. Matrix metalloproteinase proteomics: Substrates, targets, and therapy. Curr Opin Cell Biol 21: 645‐653, 2009.
 110.Mosig RA, Dowling O, DiFeo A, Ramirez MC, Parker IC, Abe E, Diouri J, Aqeel AA, Wylie JD, Oblander SA, Madri J, Bianco P, Apte SS, Zaidi M, Doty SB, Majeska RJ, Schaffler MB, Martignetti JA. Loss of MMP‐2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet 16: 1113‐1123, 2007.
 111.Mosig RA, Martignetti JA. Loss of MMP‐2 in murine osteoblasts upregulates osteopontin and bone sialoprotein expression in a circuit regulating bone homeostasis. Dis Model Mech 6: 397‐403, 2013.
 112.Mosig RA, Schulz R, Kassiri Z, Schaffler MB, Martignetti JA. Multicentric osteolysis with nodulosis, arthritis, and cardiac defect syndrome: Loss of MMP2 leads to increased apoptosis with alteration of apoptotic regulators and caspases and embryonic lethality. Adv Genom Genet 4: 207‐217, 2014.
 113.Murakami M, Sato H, Miki Y, Yamamoto K, Taketomi Y. A new era of secreted phospholipase A(2). J Lipid Res 56: 1248‐1261, 2015.
 114.Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562‐573, 2006.
 115.Noshiro M, Usui E, Kawamoto T, Kubo H, Fujimoto K, Furukawa M, Honma S, Makishima M, Honma K, Kato Y. Multiple mechanisms regulate circadian expression of the gene for cholesterol 7alpha‐hydroxylase (Cyp7a), a key enzyme in hepatic bile acid biosynthesis. J Biol Rhythms 22: 299‐311, 2007.
 116.Ou J, Tu H, Shan B, Luk A, DeBose‐Boyd RA, Bashmakov Y, Goldstein JL, Brown MS. Unsaturated fatty acids inhibit transcription of the sterol regulatory element‐binding protein‐1c (SREBP‐1c) gene by antagonizing ligand‐dependent activation of the LXR. Proc Natl Acad Sci U S A 98: 6027‐6032, 2001.
 117.Pacher P, Schulz R, Liaudet L, Szabo C. Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol Sci 26: 302‐310, 2005.
 118.Padmasekar M, Nandigama R, Wartenberg M, Schluter KD, Sauer H. The acute phase protein alpha2‐macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3‐kinase/Akt pathways. Cardiovasc Res 75: 118‐128, 2007.
 119.Park JH, Park SM, Park KH, Cho KH, Lee ST. Analysis of apolipoprotein A‐I as a substrate for matrix metalloproteinase‐14. Biochem Biophys Res Commun 409: 58‐63, 2011.
 120.Park JH, Park SM, Park SH, Cho KH, Lee ST. Cleavage and functional loss of human apolipoprotein E by digestion of matrix metalloproteinase‐14. Proteomics 8: 2926‐2935, 2008.
 121.Park JY, Park JH, Jang W, Hwang IK, Kim IJ, Kim HJ, Cho KH, Lee ST. Apolipoprotein A‐IV is a novel substrate for matrix metalloproteinases. J Biochem 151: 291‐298, 2012.
 122.Parks WC, Wilson CL, Lopez‐Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4: 617‐629, 2004.
 123.Patel J, Superko HR, Martin SS, Blumenthal RS, Christopher‐Stine L. Genetic and immunologic susceptibility to statin‐related myopathy. Atherosclerosis 240: 260‐271, 2015.
 124.Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93: 693‐704, 1998.
 125.Peng H, Liu L, Zhao X. Prognostic significance of matrix metalloproteinase‐2 in gynecological cancer: A systemic review of the literature and meta‐analysis. J BUON 18: 202‐210, 2013.
 126.Ping D, Jones PL, Boss JM. TNF regulates the in vivo occupancy of both distal and proximal regulatory regions of the MCP‐1/JE gene. Immunity 4: 455‐469, 1996.
 127.Pinto YM, Heymans S. Letter by Pinto and Heymans regarding article, “Ablation of matrix metalloproteinase‐9 increases severity of viral myocarditis in mice”. Circulation 118: e697, 2008.
 128.Prudova A, auf dem Keller U, Butler GS, Overall CM. Multiplex N‐terminome analysis of MMP‐2 and MMP‐9 substrate degradomes by iTRAQ‐TAILS quantitative proteomics. Mol Cell Proteomics 9: 894‐911, 2010.
 129.Puyraimond A, Fridman R, Lemesle M, Arbeille B, Menashi S. MMP‐2 colocalizes with caveolae on the surface of endothelial cells. Exp Cell Res 262: 28‐36, 2001.
 130.Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS. Switch‐like control of SREBP‐2 transport triggered by small changes in ER cholesterol: A delicate balance. Cell Metab 8: 512‐521, 2008.
 131.Rajamanickam C, Sakthivel S, Babu GJ, Lottspeich F, Kadenbach B. Cardiac isoform of alpha‐2 macroglobin, a novel serum protein, may induce cardiac hypertrophy in rats. Basic Res Cardiol 96: 23‐33, 2001.
 132.Rajamanickam C, Sakthivel S, Kurian Joseph P, Athimoolam Janarthanan R. A novel serum protein of molecular weight 182 kDa: A molecular marker for an early detection of increased left ventricular mass in patients with cardiac hypertrophy. J Cardiovasc Risk 5: 335‐338, 1998.
 133.Ravingerova T, Carnicka S, Nemcekova M, Ledvenyiova V, Adameova A, Kelly T, Barlaka E, Galatou E, Khandelwal VK, Lazou A. PPAR‐alpha activation as a preconditioning‐like intervention in rats in vivo confers myocardial protection against acute ischaemia‐reperfusion injury: Involvement of PI3K‐Akt. Can J Physiol Pharmacol 90: 1135‐1144, 2012.
 134.Robbesyn F, Auge N, Vindis C, Cantero AV, Barbaras R, Negre‐Salvayre A, Salvayre R. High‐density lipoproteins prevent the oxidized low‐density lipoprotein‐induced endothelial growth factor receptor activation and subsequent matrix metalloproteinase‐2 upregulation. Arterioscler Thromb Vasc Biol 25: 1206‐1212, 2005.
 135.Rodriguez D, Morrison CJ, Overall CM. Matrix metalloproteinases: What do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 1803: 39‐54, 2010.
 136.Rozanov DV, Hahn‐Dantona E, Strickland DK, Strongin AY. The low density lipoprotein receptor‐related protein LRP is regulated by membrane type‐1 matrix metalloproteinase (MT1‐MMP) proteolysis in malignant cells. J Biol Chem 279: 4260‐4268, 2004.
 137.Scherer S, de Souza TB, de Paoli J, Brenol CV, Xavier RM, Brenol JC, Chies JA, Simon D. Matrix metalloproteinase gene polymorphisms in patients with rheumatoid arthritis. Rheumatol Int 30: 369‐373, 2010.
 138.Schonbeck U, Mach F, Libby P. Generation of biologically active IL‐1 beta by matrix metalloproteinases: A novel caspase‐1‐independent pathway of IL‐1 beta processing. J Immunol 161: 3340‐3346, 1998.
 139.Schulz R. Intracellular targets of matrix metalloproteinase‐2 in cardiac disease: Rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 47: 211‐242, 2007.
 140.Selvais C, D'Auria L, Tyteca D, Perrot G, Lemoine P, Troeberg L, Dedieu S, Noel A, Nagase H, Henriet P, Courtoy PJ, Marbaix E, Emonard H. Cell cholesterol modulates metalloproteinase‐dependent shedding of low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) and clearance function. FASEB J 25: 2770‐2781, 2011.
 141.Shen M, Lee J, Basu R, Sakamuri SS, Wang X, Fan D, Kassiri Z. Divergent roles of matrix metalloproteinase 2 in pathogenesis of thoracic aortic aneurysm. Arterioscler Thromb Vasc Biol 35: 888‐898, 2015.
 142.Shiryaev SA, Remacle AG, Golubkov VS, Ingvarsen S, Porse A, Behrendt N, Cieplak P, Strongin AY. A monoclonal antibody interferes with TIMP‐2 binding and incapacitates the MMP‐2‐activating function of multifunctional, pro‐tumorigenic MMP‐14/MT1‐MMP. Oncogenesis 2: e80, 2013.
 143.Shu H, Wong B, Zhou G, Li Y, Berger J, Woods JW, Wright SD, Cai TQ. Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP‐1 cells. Biochem Biophys Res Commun 267: 345‐349, 2000.
 144.Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS. Sequence identity between the alpha 2‐macroglobulin receptor and low density lipoprotein receptor‐related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 265: 17401‐17404, 1990.
 145.Stroup D, Crestani M, Chiang JY. Identification of a bile acid response element in the cholesterol 7 alpha‐hydroxylase gene CYP7A. Am J Physiol 273: G508‐G517, 1997.
 146.Takawale A, Sakamuri SS, Kassiri Z. Extracellular matrix communication and turnover in cardiac physiology and pathology. Compr Physiol 5: 687‐719, 2015.
 147.Teres S, Barcelo‐Coblijn G, Benet M, Alvarez R, Bressani R, Halver JE, Escriba PV. Oleic acid content is responsible for the reduction in blood pressure induced by olive oil. Proc Natl Acad Sci U S A 105: 13811‐13816, 2008.
 148.Thompson PD, Clarkson P, Karas RH. Statin‐associated myopathy. JAMA 289: 1681‐1690, 2003.
 149.Turner NA, O'Regan DJ, Ball SG, Porter KE. Simvastatin inhibits MMP‐9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP‐9 mRNA levels. FASEB J 19: 804‐806, 2005.
 150.Tuysuz B, Mosig R, Altun G, Sancak S, Glucksman MJ, Martignetti JA. A novel matrix metalloproteinase 2 (MMP2) terminal hemopexin domain mutation in a family with multicentric osteolysis with nodulosis and arthritis with cardiac defects. Eur J Hum Genet 17: 565‐572, 2009.
 151.Ushio‐Fukai M. Localizing NADPH oxidase‐derived ROS. Sci STKE 2006: re8, 2006.
 152.Van den Steen PE, Van Aelst I, Hvidberg V, Piccard H, Fiten P, Jacobsen C, Moestrup SK, Fry S, Royle L, Wormald MR, Wallis R, Rudd PM, Dwek RA, Opdenakker G. The hemopexin and O‐glycosylated domains tune gelatinase B/MMP‐9 bioavailability via inhibition and binding to cargo receptors. J Biol Chem 281: 18626‐18637, 2006.
 153.Van Hul M, Bauters D, Himmelreich U, Kindt N, Noppen B, Vanhove M, Lijnen HR. Effect of gelatinase inhibition on adipogenesis and adipose tissue development. Clin Exp Pharmacol Physiol 39: 49‐56, 2012.
 154.Van Hul M, Bauters D, Lijnen RH. Differential effects of a gelatinase inhibitor on adipocyte differentiation and adipose tissue development. Clin Exp Pharmacol Physiol 40: 689‐697, 2013.
 155.Van Hul M, Lijnen HR. A functional role of gelatinase A in the development of nutritionally induced obesity in mice. J Thromb Haemost 6: 1198‐1206, 2008.
 156.Van Hul M, Lijnen HR. Effect of weight loss on gelatinase levels in obese mice. Clin Exp Pharmacol Physiol 38: 647‐649, 2011.
 157.Van Hul M, Piccard H, Lijnen HR. Gelatinase B (MMP‐9) deficiency does not affect murine adipose tissue development. Thromb Haemost 104: 165‐171, 2010.
 158.Velasco G, Pendas AM, Fueyo A, Knauper V, Murphy G, Lopez‐Otin C. Cloning and characterization of human MMP‐23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem 274: 4570‐4576, 1999.
 159.Vinet L, Rouet‐Benzineb P, Marniquet X, Pellegrin N, Mangin L, Louedec L, Samuel JL, Mercadier JJ. Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction. Am J Physiol Heart Circ Physiol 295: H352‐H360, 2008.
 160.Wahli W, Braissant O, Desvergne B. Peroxisome proliferator activated receptors: Transcriptional regulators of adipogenesis, lipid metabolism and more. Chem Biol 2: 261‐266, 1995.
 161.Wang X, Berry E, Hernandez‐Anzaldo S, Sun D, Adijiang A, Li L, Zhang D, Fernandez‐Patron C. MMP‐2 inhibits PCSK9‐induced degradation of the LDL receptor in Hepa1‐c1c7 cells. FEBS Lett 589: 490‐496, 2015.
 162.Wang X, Berry E, Hernandez‐Anzaldo S, Takawale A, Kassiri Z, Fernandez‐Patron C. Matrix metalloproteinase‐2 mediates a mechanism of metabolic cardioprotection consisting of negative regulation of the sterol regulatory element‐binding protein‐2/3‐hydroxy‐3‐methylglutaryl‐CoA reductase pathway in the heart. Hypertension 65: 882‐888, 2015.
 163.Westermann D, Savvatis K, Lindner D, Zietsch C, Becher PM, Hammer E, Heimesaat MM, Bereswill S, Volker U, Escher F, Riad A, Plendl J, Klingel K, Poller W, Schultheiss HP, Tschope C. Reduced degradation of the chemokine MCP‐3 by matrix metalloproteinase‐2 exacerbates myocardial inflammation in experimental viral cardiomyopathy. Circulation 124: 2082‐2093, 2011.
 164.Ye S. Polymorphism in matrix metalloproteinase gene promoters: Implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol 19: 623‐629, 2000.
 165.Zeng S, Zhou X, Tu Y, Yao M, Han ZQ, Gao F, Li YM. Long‐term MMP inhibition by doxycycline exerts divergent effect on ventricular extracellular matrix deposition and systolic performance in stroke‐prone spontaneously hypertensive rats. Clin Exp Hypertens 33: 316‐324, 2011.
 166.Zhang Y, Breevoort SR, Angdisen J, Fu M, Schmidt DR, Holmstrom SR, Kliewer SA, Mangelsdorf DJ, Schulman IG. Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. J Clin Invest 122: 1688‐1699, 2012.
 167.Zucker S, Conner C, DiMassmo BI, Ende H, Drews M, Seiki M, Bahou WF. Thrombin induces the activation of progelatinase A in vascular endothelial cells. Physiologic regulation of angiogenesis. J Biol Chem 270: 23730‐23738, 1995.
 168.Zucker S, Pei D, Cao J, Lopez‐Otin C. Membrane type‐matrix metalloproteinases (MT‐MMP). Curr Top Dev Biol 54: 1‐74, 2003.

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Carlos Fernandez‐Patron, Zamaneh Kassiri, Dickson Leung. Modulation of Systemic Metabolism by MMP‐2: From MMP‐2 Deficiency in Mice to MMP‐2 Deficiency in Patients. Compr Physiol 2016, 6: 1935-1949. doi: 10.1002/cphy.c160010