Abstract
Atherosclerosis is a major cause of coronary heart disease, and matrix metalloproteinases (MMPs) play an important role in atherosclerosis by degrading the extracellular matrix, which results in cardiovascular remodeling. Recent studies have identified enhanced expression of MMPs in the atherosclerotic lesion and their contribution to weakening of the vascular wall by degrading the extracellular matrix. The transcription, enzyme processing, and specific inhibition of MMPs by tissue inhibitors of matrix metalloproteinase (TIMPs) regulate these effects. These processes are also modified by inflammatory cytokines and cell-cell contact signaling. Both animal experiments and clinical sample analysis have shown that balance in expression and activation of MMPs and inhibition by TIMPs is critical for the development of stenotic and aneurysmal change. Polymorphism in the MMP gene promoter contributes to inter-individual differences in susceptibility to coronary heart disease. The development of therapeutic drugs specifically targeting MMPs may thus be useful for the prevention of atherosclerotic lesion progression, plaque rupture, and restenosis.
Similar content being viewed by others
References
Massova I, Kotra LP, Fridman R, Mobashery S: Matrix metalloproteinases: structures, evolution, and diversification. FASEB J 1998, 12:1075–1095.
Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002, 115:3719–3727.
Creemers EE, Cleutjens JP, Smits JF, Daemen MJ: Matrix metal-loproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res 2001, 89:201–210.
Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003, 92:827–839.
Martignetti JA, Aqeel AA, Sewairi WA, et al.: Mutation of the matrix metalloproteinase 2 gene (mmp2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 2001, 28:261–265.
Nagase H, Woessner JF Jr: Matrix metalloproteinases. J Biol Chem 1999, 274:21491–21494.
Hojo Y, Ikeda U, Takahashi M, et al.: Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells. J Mol Cell Cardiol 2000, 32:1459–1468.
Lijnen HR: Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 2001, 86:324–333.
Rajagopalan S, Meng XP, Ramasamy S, et al.: Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 1996, 98:2572–2579.
Xu XP, Meisel SR, Ong JM, et al.: Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation 1999, 99:993–998.
Sato H, Kinoshita T, Takino T, et al.: Activation of a recombinant membrane type 1-matrix metalloproteinase (mt1-mmp) by furin and its interaction with tissue inhibitor of metallo-proteinases (timp)-2. FEBS Lett 1996, 393:101–104.
Murphy G, Stanton H, Cowell S, et al.: Mechanisms for pro matrix metalloproteinase activation. Acta Pathol Microbiol Immunol Scand 1999, 107:38–44.
John A, Tuszynski G: The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 2001, 7:14–23.
Lacraz S, Nicod LP, Chicheportiche R, et al.: I1-10 inhibits metalloproteinase and stimulates timp-1 production in human mononuclear phagocytes. J Clin Invest 1995, 96:2304–2310.
Shapiro SD, Campbell EJ, Kobayashi DK, Welgus HG: Immune modulation of metalloproteinase production in human macrophages. Selective pretranslational suppression of interstitial collagenase and stromelysin biosynthesis by interferon-gamma. J Clin Invest 1990, 86:1204–1210.
Ikeda U, Takahashi M, Shimada K: Monocyte-endothelial cell interaction in atherogenesis and thrombosis. Clin Cardiol 1998, 21:11–14.
Magid R, Murphy TJ, Galis ZS: Expression of matrix metalloproteinase-9 in endothelial cells is differentially regulated by shear stress. Role of c-myc. J Biol Chem 2003, 278:32994–32999.
Death AK, Fisher EJ, McGrath KC, Yue DK: High glucose alters matrix metalloproteinase expression in two key vascular cells: Potential impact on atherosclerosis in diabetes. Atherosclerosis 2003, 168:263–269.
Rodriguez-Nieto S, Chavarria T, Martinez-Poveda B, et al.: Anti-angiogenic effects of homocysteine on cultured endothelial cells. Biochem Biophys Res Commun 2002, 293:497–500.
Kishi J, Hayakawa T: Synthesis of latent collagenase and collagenase inhibitor by bovine aortic medial explants and cultured medial smooth muscle cells. Connect Tissue Res 1989, 19:63–76.
Galis ZS, Khatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002, 90:251–262.
Galis ZS, Sukhova GK, Kranzhofer R, et al.: Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci U S A 1995, 92:402–406.
Shah PK, Falk E, Badimon JJ, et al.: Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 1995, 92:1565–1569.
George SJ, Zaltsman AB, Newby AC: Surgical preparative injury and neointima formation increase mmp-9 expression and mmp-2 activation in human saphenous vein. Cardiovasc Res 1997, 33:447–459.
Kranzhofer A, Baker AH, George SJ, Newby AC: Expression of tissue inhibitor of metalloproteinase-1, -2, and -3 during neointima formation in organ cultures of human saphenous vein. Arterioscler Thromb Vasc Biol 1999, 19:255–265.
Lamfers ML, Grimbergen JM, Aalders MC, et al.: Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor timp-1.Atf suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1. Circ Res 2002, 91:945–952.
Zempo N, Kenagy RD, Au YP, et al.: Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg 1994, 20:209–217.
Strauss BH, Robinson R, Batchelor WB, et al.: In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. Circ Res 1996, 79:541–550.
Bendeck MP, Conte M, Zhang M, et al.: Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury. Am J Pathol 2002, 160:1089–1095.
Zempo N, Koyama N, Kenagy RD, et al.: Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor. Arterioscler Thromb Vasc Biol 1996, 16:28–33.
Bendeck MP, Irvin C, Reidy MA: Inhibition of matrix metallo-proteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res 1996, 78:38–43.
Mason DP, Kenagy RD, Hasenstab D, et al.: Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res 1999, 85:1179–1185.
Dollery CM, Humphries SE, McClelland A, et al.: Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury. Circulation 1999, 99:3199–3205.
Furman C, Luo Z, Walsh K, et al.: Systemic tissue inhibitor of metalloproteinase-1 gene delivery reduces neointimal hyperplasia in balloon-injured rat carotid artery. FEBS Lett 2002, 531:122–126.
Bassiouny HS, Song RH, Hong XF, et al.: Flow regulation of 72-kd collagenase iv (mmp-2) after experimental arterial injury. Circulation 1998, 98:157–163.
Hu Y, Baker AH, Zou Y, et al.: Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model. Arterioscler Thromb Vasc Biol 2001, 21:1275–1280.
Chesler NC, Ku DN, Galis ZS: Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo. Am J Physiol 1999, 277:H2002-H2009.
Petrinec D, Liao S, Holmes DR, et al.: Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kd gelatinase. J Vasc Surg 1996, 23:336–346.
Freestone T, Turner RJ, Higman DJ, et al.: Influence of hypercholesterolemia and adventitial inflammation on the development of aortic aneurysm in rabbits. Arterioscler Thromb Vasc Biol 1997, 17:10–17.
Bigatel DA, Elmore JR, Carey DJ, et al.: The matrix metalloproteinase inhibitor bb-94 limits expansion of experimental abdominal aortic aneurysms. J Vasc Surg 1999, 29:130–138; discussion 138–139.
Allaire E, Forough R, Clowes M, et al.: Local overexpression of timp-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 1998, 102:1413–1420.
Cai W, Vosschulte R, Afsah-Hedjri A, et al.: Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis. J Mol Cell Cardiol 2000, 32:997–1011.
Morishige K, Shimokawa H, Matsumoto Y, et al.: Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo. Cardiovasc Res 2003, 57:572–585.
Praul CA, Ford BC, Gay CV, et al.: Gene expression and tibial dyschondroplasia. Poult Sci 2000, 79:1009–1013.
Rouis M, Adamy C, Duverger N, et al.: Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein e-deficient mice. Circulation 1999, 100:533–540.
Kuzuya M, Kanda S, Sasaki T, et al.: Deficiency of gelatinase a suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia. Circulation 2003, 25:25.
Silence J, Lupu F, Collen D, Lijnen HR: Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (mmp-3) gene inactivation. Arterioscler Thromb Vasc Biol 2001, 21:1440–1445.
Galis ZS, Johnson C, Godin D, et al.: Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 2002, 91:852–859.
Lijnen HR, Van Hoef B, Vanlinthout I, et al.: Accelerated neointima formation after vascular injury in mice with stromelysin-3 (mmp-11) gene inactivation. Arterioscler Thromb Vasc Biol 1999, 19:2863–2870.
Silence J, Collen D, Lijnen HR: Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (timp-1) gene. Circ Res 2002, 90:897–903.
Newman KM, Malon AM, Shin RD, et al.: Matrix metalloproteinases in abdominal aortic aneurysm: Characterization, purification, and their possible sources. Connect Tissue Res 1994, 30:265–276.
Carrell TW, Burnand KG, Wells GM, et al.: Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms. Circulation 2002, 105:477–482.
Thompson RW, Parks WC: Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann N Y Acad Sci 1996, 800:157–174.
Baxter BT, Pearce WH, Waltke EA, et al.: Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (phase ii) multicenter study. J Vasc Surg 2002, 36:1–12.
Sangiorgi G, D’Averio R, Mauriello A, et al.: Plasma levels of metalloproteinases-3 and -9 as markers of successful abdominal aortic aneurysm exclusion after endovascular graft treatment. Circulation 2001, 104:I288-I295.
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 1994, 94:2493–2503.
Galis ZS, Sukhova GK, Libby P: Microscopic localization of active proteases by in situ zymography: Detection of matrix metalloproteinase activity in vascular tissue. FASEB J 1995, 9:974–980.
Hower CD, Dassow MS, Kajdacsy-Balla A, et al.: Metalloproteinase levels are decreased in symptomatic carotid plaques. J Surg Res 2000, 88:155–159.
Loftus IM, Naylor AR, Bell PR, Thompson MM: Matrix metalloproteinases and atherosclerotic plaque instability. Br J Surg 2002, 89:680–694.
Beaudeux JL, Giral P, Bruckert E, et al.: Serum matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 as potential markers of carotid atherosclerosis in infraclinical hyperlipidemia. Atherosclerosis 2003, 169:139–146.
Loftus IM, Goodall S, Crowther M, et al.: Increased mmp-9 activity in acute carotid plaques: Therapeutic avenues to prevent stroke. Ann N Y Acad Sci 1999, 878:551–554.
Crisby M, Nordin-Fredriksson G, Shah PK, et al.: Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: Implications for plaque stabilization. Circulation 2001, 103:926–933.
Axisa B, Loftus IM, Naylor AR, et al.: Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques. Stroke 2002, 33:2858–2864.
Henney AM, Wakeley PR, Davies MJ, et al.: Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A 1991, 88:8154–8158.
Schoenhagen P, Vince DG, Ziada KM, et al.: Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary atherectomy to intravascular ultrasound observations on coronary remodeling. Am J Cardiol 2002, 89:1354–1359.
Brown DL, Hibbs MS, Kearney M, et al.: Identification of 92-kd gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation 1995, 91:2125–2131.
Lee RT, Schoen FJ, Loree HM, et al.: Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis. Implications for plaque rupture. Arterioscler Thromb Vasc Biol 1996, 16:1070–1073.
Kai H, Ikeda H, Yasukawa H, et al.: Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998, 32:368–372.
Hojo Y, Ikeda U, Ueno S, et al.: Expression of matrix metalloproteinases in patients with acute myocardial infarction. Jpn Circ J 2001, 65:71–75.
Kalela A, Koivu TA, Sisto T, et al.: Serum matrix metalloproteinase-9 concentration in angiographically assessed coronary artery disease. Scand J Clin Lab Invest 2002, 62:337–342.
Bellosta S, Via D, Canavesi M, et al.: Hmg-coa reductase inhibitors reduce mmp-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998, 18:1671–1678.
Ikeda U, Shimpo M, Ohki R, et al.: Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension 2000, 36:325–329.
Ikeda U, Shimada K: Pleiotropic effects of statins on the vascular tissue. Curr Drug Targets Cardiovasc Haematol Disord 2001, 1:51–58.
Koh KK, Son JW, Ahn JY, et al.: Comparative effects of diet and statin on no bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002, 22:e19-e23.
Ikeda U, Hojo Y, Ueno S, et al.: Amlodipine inhibits expression of matrix metalloproteinase-1 and its inhibitor in human vascular endothelial cells. J Cardiovasc Pharmacol 2000, 35:887–890.
Bellosta S, Canavesi M, Favari E, et al.: Lacidipine [correction of lalsoacidipine] modulates the secretion of matrix metalloproteinase-9 by human macrophages. J Pharmacol Exp Ther 2001, 296:736–743.
Sawicki G, Salas E, Murat J, et al.: Release of gelatinase a during platelet activation mediates aggregation. Nature 1997, 386:616–619.
Hojo Y, Ikeda U, Katsuki T, et al.: Matrix metalloproteinase expression in the coronary circulation induced by coronary angioplasty. Atherosclerosis 2002, 161:185–192.
Ye S: Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol 2000, 19:623–629.
Ye S, Watts GF, Mandalia S, et al.: Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995, 73:209–215.
Ye S, Eriksson P, Hamsten A, et al.: Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996, 271:13055–13060.
Pollanen PJ, Lehtimaki T, Ilveskoski E, et al.: Coronary artery calcification is related to functional polymorphism of matrix metalloproteinase 3: The Helsinki Sudden Death study. Atherosclerosis 2002, 164:329–335.
Beyzade S, Zhang S, Wong YK, et al.: Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol 2003, 41:2130–2137.
Cho HJ, Chae IH, Park KW, et al.: Functional polymorphism in the promoter region of the gelatinase b gene in relation to coronary artery disease and restenosis after percutaneous coronary intervention. J Hum Genet 2002, 47:88–91.
Morgan AR, Zhang B, Tapper W, et al.: Haplotypic analysis of the mmp-9 gene in relation to coronary artery disease. J Mol Med 2003, 81:321–326.
Jormsjo S, Ye S, Moritz J, et al.: Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ Res 2000, 86:998–1003.
Jormsjo S, Whatling C, Walter DH, et al.: Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2001, 21:1834–1839.
Wang X, Tromp G, Cole CW, et al.: Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (timp1) and 2 (timp2) in patients with aneurysms. Matrix Biol 1999, 18:121–124.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Watanabe, N., Ikeda, U. Matrix metalloproteinases and atherosclerosis. Curr Atheroscler Rep 6, 112–120 (2004). https://doi.org/10.1007/s11883-004-0099-1
Issue Date:
DOI: https://doi.org/10.1007/s11883-004-0099-1