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. 2006 Dec 5;26(2):55–59. doi: 10.1002/clc.4960260203

Matrix metalloproteinases and coronary artery diseases

Uichi Ikeda 1,✉, Kazuyuki Shimada 1
PMCID: PMC6654730  PMID: 12625594

Abstract

Matrix metalloproteinases (MMPs) play an important role in cardiovascular remodeling by degrading the extracellular matrix. Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis.

Keywords: atherosclerosis, cute coronary syndrome, restenosis, plaque rupture

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References

  • 1. Creemers EEJM, Cleutjens JPM, Smits JFM, Daemen MJAP: Matrix metalloproteinase inhibition after myocardial infarction: A new approach to prevent heart failure. Circ Res 2001; 89: 201–210 [DOI] [PubMed] [Google Scholar]
  • 2. Lijnen HR, Collen D: Matrix metalloproteinase system deficiencies and matrix degradation. Thromb Haemost 1999; 82: 837–845 [PubMed] [Google Scholar]
  • 3. Dollery CM, McEwan JR, Henney AM: Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77: 863–868 [DOI] [PubMed] [Google Scholar]
  • 4. George SJ: Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Exp Opin Invest Drugs 2000; 9: 993–1007 [DOI] [PubMed] [Google Scholar]
  • 5. Lacraz S, Nicod LP, Chicheportiche R, Welgus HG, Dayer JM: IL‐10 inhibits metalloproteinase and stimulates TIMP‐1 production in human mononuclear phagocytes. J Clin Invest 1995; 96: 2304–2310 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Sasaguri T, Arima N, Tanimoto A, Shimajiri S, Hamada T, Sasaguri Y: A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. Atherosclerosis 1998; 138: 247–253 [DOI] [PubMed] [Google Scholar]
  • 7. Shapiro SD, Campbell EJ, Kobayashi DK, Welgus HG: Immune modulation of metalloproteinase production in human macrophages. Selective pre‐translational suppression of interstitial collagenase and stromelysin biosynthesis by interferon‐γ. J Clin Invest 1990; 86: 1204–1210 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Malik N, Greenfield BW, Wahl AF, Kiener PA: Activation of human monocytes through CD40 induces matrix metalloproteinases. J Immunol 1996; 156: 3952–3960 [PubMed] [Google Scholar]
  • 9. Schonbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi RP, Libby P: Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by lymphocytes. A role for CD40 signaling in plaque rupture? Circ Res 1997; 81: 448–454 [DOI] [PubMed] [Google Scholar]
  • 10. Lee E, Grodzinsky AJ, Libby P, Clinton SK, Lark MW, Lee RT: Human vascular smooth muscle cell‐monocyte interactions and metalloproteinase secretion in culture. Arterioscler Thromb Vasc Biol 1995; 15: 2284–2289 [DOI] [PubMed] [Google Scholar]
  • 11. Hojo Y, Ikeda U, Takahashi M, Sakata Y, Takizawa T, Okada K, Saito T, Shimada K: Matrix metalloproteinase‐1 expression by interaction between monocytes and vascular endothelial cells. J Mol Cell Cardiol 2000; 32: 1459–1468 [DOI] [PubMed] [Google Scholar]
  • 12. Lijnen HR: Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 2001; 86: 324–333 [PubMed] [Google Scholar]
  • 13. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS: Reactive oxygen species produced by macrophage‐derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. J Clin Invest 1996; 98: 2572–2579 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. 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 1998; 97: 2445–2453 [DOI] [PubMed] [Google Scholar]
  • 15. Xu XP, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth TB, Sharifi B, Shah PK: Oxidized low‐density lipoprotein regulates matrix metallopro‐teinase‐9 and its tissue inhibitor in human monocyte‐derived macrophages. Circulation 1999; 99: 993–998 [DOI] [PubMed] [Google Scholar]
  • 16. Ikeda U, Takahashi M, Shimada K: Monocyte‐endothelial cell interaction in atherogenesis and thrombosis. Clin Cardiol 1998; 21: 11–14 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Lijnen HR, Van Hoef B, Lupu F, Moons L, Carmeliet P, Collen D: Function of the plasminogen/plasmin and matrix metalloproteinase systems after vascular injury in mice with targeted inactivation of fibrinolytic system genes. Arterioscler Thromb Vasc Biol 1998; 18: 1035–1045 [DOI] [PubMed] [Google Scholar]
  • 18. Lijnen HR, Soloway P, Collen D: Tissue inhibitor of matrix metalloproteinase‐1 impairs arterial neointima formation after vascular injury in mice. Circ Res 1999; 85: 1186–1191 [DOI] [PubMed] [Google Scholar]
  • 19. Galis ZS, Sukhova GK, Kranzohofer R, Clark S, Libby P: Macrophage foam cells from experimental atheroma constitutively produce matrix‐degrading proteinases. Proc Natl Acad Sci USA 1995; 92: 402–406 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Shah PK, Falk E, Badimon JJ, Fernandez‐Ortiz A, Mailhac A, Villareal‐Levy G, Fallon JT, Regnstrom J, Fuster V: Human monocyte‐derived macrophages induce collagen breakdown in fibrous caps of atheroslcerotic plaques: Potential role of matrix‐degrading metalloproteinases and implications for plaque rupture. Circulation 1995; 92: 1565–1569 [PubMed] [Google Scholar]
  • 21. Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R, Murphy G, Humphries S: Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA 1991; 88: 8145–8158 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atheroslcerotic plaques. J Clin Invest 1994; 94: 2493–2503 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Galis ZS, Muszynski M, Sukhova GK, Simon‐Morrissey E, Libby P: Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann N Y Acad Sci 1995; 748: 501–507 [DOI] [PubMed] [Google Scholar]
  • 24. Nikkari ST, O'Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, Clowes AW: Interstitial collagenase (MMP‐1) expression in human carotid atherosclerosis. Circulation 1995; 92: 1393–1398 [DOI] [PubMed] [Google Scholar]
  • 25. Halpert I, Sires UI, Roby JD, Potter‐Perigo S, Wight TN, Shapiro SD, Welgus HG, Wickline SA, Parks WC: Matrilysin is expressed by lipid‐laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci USA 1996; 93: 9748–9753 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Li Z, Li L, Zielke HR, Cheng L, Xiao R, Crow MT, Stetler‐Stevenson WG, Froehlich J, Lakatta EG: Increased expression of 72‐kd type IV collagenase (MMP‐2) in human atherosclerotic lesions. Am J Pathol 1996; 148: 121–128 [PMC free article] [PubMed] [Google Scholar]
  • 27. Pasterkamp G, Schoneveld AH, Hijnen DJ, de Kleijn DP, Teepen H, van der Wal AC, Borst C: Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery. Atherosclerosis 2000; 150: 245–253 [DOI] [PubMed] [Google Scholar]
  • 28. Pasterkamp JG, Schoneveld AH, Hijnen DJ, de Kleijn DPV, Teepen H, van der Wal AC, Borst C: Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteinases 1, 2 and 9 in the human coronary artery. Atherosclerosis 2000; 150: 245–253 [DOI] [PubMed] [Google Scholar]
  • 29. Shu YE, Humphries S, Henney A: Matrix metalloproteinases: Implication in vascular matrix remodeling during atherogenesis. Clin Sci 1998; 94: 103–110 [DOI] [PubMed] [Google Scholar]
  • 30. Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R: Matrix metalloproteinase‐2 contributes to ischemia‐reperfusion injury in the heart. Circulation 2000; 101: 1833–1839 [DOI] [PubMed] [Google Scholar]
  • 31. Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM: Identification of 92‐kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation 1995; 91: 2125–2131 [DOI] [PubMed] [Google Scholar]
  • 32. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, Ueno T, Sugi K, Imaizumi T: Peripheral blood levels of matrix metalloproteinases‐2 and 9 are elevated in patients with acute myocardial syndrome. J Am Coll Cardiol 1998; 32: 368–372 [DOI] [PubMed] [Google Scholar]
  • 33. Inokubo Y, Hanada H, Ishizaka H, Fukushi T, Kamada T, Okumura K: Plasma levels of matrix metalloproteinase‐9 and tissue inhibitor of metallo‐proteinase‐1 are increased in the coronary circulation in patients with acute coronary syndrome. Am Heart J 2001; 141: 211–217 [DOI] [PubMed] [Google Scholar]
  • 34. Hirohata S, Kusachi S, Murakami M, Murakami T, Sano I, Watanabe T, Komatsubara I, Kondo J, Tsuji T: Time dependent alterations of serum matrix metalloproteinase‐1 and metalloproteinase‐1 tissue inhibitor after successful reperfusion of acute coronary syndrome. Heart 1997; 78: 278–284 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Hojo Y, Ikeda U, Ueno S, Arakawa H, Shimada K: Expression of matrix metalloproteinases in patients with acute myocardial infarction. Jpn Circ J 2001; 65: 71–75 [DOI] [PubMed] [Google Scholar]
  • 36. James TW, Wagner R, White LA, Zwolak RM, Brinkerhoff CE: Induction of collagenase and stromelysin gene expression by mechanical injury in vascular smooth muscle‐derived cell line. J Cell Physiol 1993; 157: 426–437 [DOI] [PubMed] [Google Scholar]
  • 37. Bendeck MP, Zempo N, Clowes AV, Galardy RE, Reidy MA: Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 1994; 75: 539–545 [DOI] [PubMed] [Google Scholar]
  • 38. Southgate KM, Fisher M, Banning AP, Thurston VJ, Baker AH, Fabunmi RP, Grove PH, Davies M, Newby AC: Upregulation of basement membrane‐degrading metalloproteinase secretion after balloon injury of pig carotid arteries. Circ Res 1996; 79: 1177–1187 [DOI] [PubMed] [Google Scholar]
  • 39. Sawicki G, Salas E, Murat J, Miszta‐Lane H, Radomski MW: Release of gelatinase A during platelet activation mediates aggregation. Nature 1997; 386: 616–619 [DOI] [PubMed] [Google Scholar]
  • 40. Cheng L, Mantile G, Pauly R, Nater C, Felici A, Monticone R, Bilato C, Gluzband YA, Crow MT, Stetler‐Stevenson W, Capogrossi MC: Adenovirus‐mediated gene transfer of the human tissue inhibitor of metalloproteinase‐2 blocks vascular smooth muscle cell invasiveness in vitro and modulates neointimal development in vivo. Circulation 1998; 98: 2195–2201 [DOI] [PubMed] [Google Scholar]
  • 41. Hojo Y, Ikeda U, Katsuki T, Mizuno O, Fujikawa H, Shimada K: Matrix metalloproteinase expression in the coronary circulation induced by coronary angioplasty. Atherosclerosis 2002; 161: 185–192 [DOI] [PubMed] [Google Scholar]
  • 42. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini F: HMG‐CoA reductase inhibitors reduce MMP‐9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998; 18: 1671–1678 [DOI] [PubMed] [Google Scholar]
  • 43. Ikeda U, Shimpo M, Ohki R, Inaba H, Takahashi M, Yamamoto K, Shim‐ada K: Fluvastatin inhibits matrix metalloproteinase‐1 expression in human vascular endothelial cells. Hypertension 2000; 36: 325–329 [DOI] [PubMed] [Google Scholar]
  • 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 2001; 103: 993–999 [DOI] [PubMed] [Google Scholar]
  • 45. Ikeda U, Shimada K: Pleiotropic effects of statins on the vascular tissue. Curr Drug Targets‐Cardiovasc Haematol Dis 2001; 1: 51–58 [DOI] [PubMed] [Google Scholar]
  • 46. Mason PP, Walter MF, Trumbore MW, Olmstead EG Jr, Mason PE: Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine. J Mol Cell Cardiol 1993; 31: 275–281 [DOI] [PubMed] [Google Scholar]
  • 47. Ikeda U, Hojo Y, Ueno S, Arakawa H, Shimada K: Amlodipine inhibits expression of matrix metalloproteinase‐1 and its inhibitor in human endothelial cells. J Cardiovasc Pharmacol 2000; 35: 887–890 [DOI] [PubMed] [Google Scholar]
  • 48. Herbette LG, Gaviraghi G, Tulenko T, Mason RP: Molecular interaction between lacidipine and biological membranes. J Hypertens 1993; 11: S13–19 [DOI] [PubMed] [Google Scholar]
  • 49. Bellosta S, Canavesi M, Favari E, Cominacini L, Gaviraghi G, Fumagalli R, Paoletti R, Bernini F: Lalsoacidipine modulates the secretion of matrix met‐alloproteinase‐9 by human macrophages. J Pharmacol Exp Ther 2001; 296: 736–743 [PubMed] [Google Scholar]
  • 50. Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GBJ, Miller ME, Riley W: Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102: 1503–1510 [DOI] [PubMed] [Google Scholar]
  • 51. Jorgensen B, Simonsen S, Endresen K, Forfang K, Vatne K, Hansen J, Webb J, Buller C, Goulet G, Erikssen J, Thaulow E: Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: Results from the Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES). J Am Coll Cardiol 2000; 35: 592–599 [DOI] [PubMed] [Google Scholar]
  • 52. Forough R, Koyama N, Hasenstab D, Lea H, Clowes M, Nikkari ST, Clowes AW: Overexpression of tissue inhibitor of matrix metallopro‐teinase‐1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ Res 1996; 79: 812–820 [DOI] [PubMed] [Google Scholar]
  • 53. Dollery CM, Humphries SE, McClelland A, Latchman DS, McEwan JR: Expression of tissue inhibitor of matrix metalloproteinase 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 [DOI] [PubMed] [Google Scholar]
  • 54. Rouis M, Adamy C, Duverger N, Lesnik P, Horellou P, Moreau M, Emmanuel F, Caillaud JM, Laplaud PM, Dachet C, Chapman MJ: Adenovirus‐mediated overexpression of tissue inhibitor of metalloproteinase‐1 reduces atherosclerotic lesions in apolipoprotein E‐deficient mice. Circulation 1999; 100: 533–540 [DOI] [PubMed] [Google Scholar]
  • 55. George SJ, Lloyd CT, Angelini GD, Newby AC, Baker AH: Inhibition of late vein graft neointimal formation in human and porcine models by adenovirus‐mediated overexpression of tissue inhibitor of metalloproteinase‐3. Circulation 2000; 101: 296–304 [DOI] [PubMed] [Google Scholar]
  • 56. George SJ, Johnson JL, Angelini GD, Newby AC, Baker AH: Adenovirus‐mediated gene transfer of the human TIMP‐1 gene inhibits smooth muscle cell migration and neointimal formation in human saphenous vein. Hum Gene Ther 1998; 9: 867–877 [DOI] [PubMed] [Google Scholar]

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