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Matrix metalloproteinases and peripheral arterial disease

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An Erratum to this article was published on 24 September 2009

Abstract

Matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix, are emerging as important modulators of atherothrombosis. MMPs are produced by inflammatory cells; some of them are also released by activated platelets and play a crucial role in the remodeling processes, leading to atherosclerotic plaque formation, plaque rupture, arterial aneurysm development, and critical limb ischemia. Independent from their matrix degrading activity, MMPs also regulate some cell functions relevant to atherothrombosis, such as platelet activation, neutrophil activation, and vascular reactivity. Plasma levels of some MMPs are increasingly being recognized as a biomarker of atherosclerosis and cardiovascular risk. In peripheral arterial disease, MMPs have been shown to be involved in angiogenesis, arteriogenesis, and the development of arterial calcifications. Increased plasma levels of some MMPs (MMP-2, MMP-9) have been correlated with PAD development and severity. Single nucleotide polymorphisms of the genes encoding for some MMPs have also been associated with the risk of developing peripheral arterial disease and critical limb ischemia. Large prospective observational studies are needed to further demonstrate the role of MMPs in PAD. In perspective, pharmacologic targeting of the expression or activity of MMPs may represent a novel, attractive approach for the treatment of peripheral arterial disease.

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References

  1. Woessner JF (1993) Introduction to serial reviews: the extracellular matrix. FASEB J 7:735–736

    PubMed  Google Scholar 

  2. Hobeika MJ (2007) Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg 45:849–857

    Article  PubMed  Google Scholar 

  3. Newby AC (2005) Dual role of matrix metalloproteinases (Matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 85:1–31

    Article  CAS  PubMed  Google Scholar 

  4. Morgunova E, Tuuttila A, Bergmann U et al (1999) Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science 284:1667–1670

    Article  CAS  PubMed  Google Scholar 

  5. Van Wart HE, Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87:5578–5582

    Article  PubMed  Google Scholar 

  6. Bassiouny HS, Song RH, Hong XF et al (1998) Flow regulation of 72 KD-collagenase IV (MMP-2) after experimental arterial injury. Circulation 98:157–163

    CAS  PubMed  Google Scholar 

  7. Godin D, Ivan E, Johnson C et al (2000) Remodelling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation 102:2861–2866

    CAS  PubMed  Google Scholar 

  8. Chesler NC, Ku DN, Galis ZS (1999) Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo. Am J Physiol 277:H2002–H2009

    CAS  PubMed  Google Scholar 

  9. Reichenbach G, Momi S, Gresele P (2005) Nitric oxide and its antithrombotic action in the cardiovascular system. Curr Drug Targets Cardiovasc Haematol Disord 5:65–74

    Article  PubMed  Google Scholar 

  10. Rajagopalan S, Meng XP, Ramasamy S et al (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate activity of vascular matrix metalloproteinases in vitro. J Clin Invest 98:2572–2579

    Article  CAS  PubMed  Google Scholar 

  11. Frears ER, Zhang Z, Blake DR et al (1996) Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite. FEBS Lett 381:21–24

    Article  CAS  PubMed  Google Scholar 

  12. Tayebjee MH, Lip GY, Blann AD et al (2005) Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases MMP-2 and -9, and their inhibitors, tissue inhibitors of matrix metalloproteinases TIMP-1 and -2. Thromb Res 115:205–210

    Article  CAS  PubMed  Google Scholar 

  13. Ye S (2006) Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovasc Res 69:636–645

    Article  CAS  PubMed  Google Scholar 

  14. Santos-Martínez MJ, Medina C, Jurasz P et al (2008) Role of metalloproteinases in platelet function. Thromb Res 121:535–542

    Article  PubMed  Google Scholar 

  15. Sawicki G, Salas E, Murat J et al (1997) Release of gelatinase A during platelet activation mediates aggregation. Nature 386:616–619

    Article  CAS  PubMed  Google Scholar 

  16. Falcinelli E, Guglielmini G, Torti M et al (2005) Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-2 on platelet aggregation. J Thromb Haemost 3:2526–2535

    Article  CAS  PubMed  Google Scholar 

  17. Galt SW, Lindemann S, Allen L et al (2002) Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function. Circ Res 90:1093–1099

    Article  CAS  PubMed  Google Scholar 

  18. Pitchford SC, Momi S, Baglioni S et al (2008) Allergen induces the migration of platelets to lung tissue in allergic asthma. Am J Respir Crit Care Med 177:604–612

    Article  CAS  PubMed  Google Scholar 

  19. Santilli F, Basili S, Ferroni P et al (2007) CD40/CD40L system and vascular disease. Intern Emerg Med 2:256–268

    Article  CAS  PubMed  Google Scholar 

  20. Furman MI, Krueger LA, Linden MD et al (2004) Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol 43:2319–2325

    Article  CAS  PubMed  Google Scholar 

  21. Emaitre V, O’Byrne TK, Borczuk AC et al (2001) ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest 107:1227–1234

    Article  Google Scholar 

  22. Ilence J, Lupu F, Collen D et al (2001) Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol 21:1440–1445

    Article  Google Scholar 

  23. Lijnen HR, Van Hoef B, Lupu F et al (1998) 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 18:1035–1045

    CAS  PubMed  Google Scholar 

  24. Galis ZS, Sukhova GK, Lark MW et al (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503

    Article  CAS  PubMed  Google Scholar 

  25. Brown DL, Hibbs MS, Kearney M et al (1997) Differential expression of 92-kDa gelatinase in primary atherosclerotic versus restenotic coronary lesions. Am J Cardiol 79:878–882

    Article  CAS  PubMed  Google Scholar 

  26. Jones CB, Sane DC, Herrington DM (2003) Matrix metalloproteinases: a review of their structure and role in acute coronary syndromes. Cardiovasc Res 59:812–823

    Article  CAS  PubMed  Google Scholar 

  27. Hojo Y, Ikeda U, Katsuki T et al (2002) Matrix metalloproteinase expression in the coronary circulation induced by coronary angioplasty. Atherosclerosis 161:185–192

    Article  CAS  PubMed  Google Scholar 

  28. Galis ZS, Kranzhofer R, Fenton JW 2nd et al (1997) Thrombin promotes activation of matrix metalloproteinase-2 produced by cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 17:483–489

    Google Scholar 

  29. Gresele P, Falcinelli E, Momi S (2008) Potentiation and priming of platelet activation: a potential target of antiplatelet therapy. Trends Pharmacol Sci 29:352–360

    Article  CAS  PubMed  Google Scholar 

  30. Knox JB, Sukhova GK, Whittemore AD et al (1997) Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation 95:205–212

    CAS  PubMed  Google Scholar 

  31. Goodall S, Crowther M, Hemingway DM et al (2001) Ubiquitous elevation of matrix metalloproteinase-2 expression in the vasculature of patients with abdominal aneurysms. Circulation 104:304–309

    CAS  PubMed  Google Scholar 

  32. Urbonavicius S, Urbonaviciene G, Honorè B et al (2008) Potential circulating biomarkers for abdominal aortic aneurysm expansion and rupture—a systematic review. Eur J Vasc Endovasc Surg 36:273–280

    Article  CAS  PubMed  Google Scholar 

  33. Sang QX (1998) Complex role of matrix metalloproteinases in angiogenesis. Cell Res 8:171–177

    CAS  PubMed  Google Scholar 

  34. Muhs BE, Plitas G, Delgado Y et al (2003) Temporal expression and activation of matrix metalloproteinases-2, -9, and membrane type 1-matrix metalloproteinase following acute hindlimb ischemia. J Surg Res 111:8–15

    Article  CAS  PubMed  Google Scholar 

  35. Lee S, Jilani SM, Nikolova GV et al (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169:681–691

    Article  CAS  PubMed  Google Scholar 

  36. Hangai M, Kitaya N, Xu J et al (2002) Matrix metalloproteinase-9-dependent exposure of a cryptic migratory control site in collagen is required before retinal angiogenesis. Am J Pathol 161:1429–1437

    CAS  PubMed  Google Scholar 

  37. Hessig B, Hattori K, Dias S et al (2002) Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9-mediated release of kit-ligand. Cell 109:625–637

    Article  Google Scholar 

  38. Cai WJ, Koltai S, Kocsis E et al (2003) Remodeling of the adventitia during coronary arteriogenesis. Am J Physiol Heart Circ Physiol 284:H31–H40

    CAS  PubMed  Google Scholar 

  39. Jenkins GM, Crow MT, Bilato C et al (1998) Increased expression of membrane-type matrix metalloproteinase and preferential localization of matrix metalloproteinase-2 to the neointima of balloon-injured rat carotid arteries. Circulation 97:82–90

    CAS  PubMed  Google Scholar 

  40. Zang J, Nie L, Razavian M et al (2008) Molecular imaging of activated matrix metalloproteinases in vascular remodeling. Circulation 118:1953–1960

    Article  Google Scholar 

  41. Lijnen HR, Soloway P, Collen D (1999) Tissue inhibitor of matrix metalloproteinases-1 impairs arterial neointima formation after vascular injury in mice. Circ Res 85:1186–1191

    CAS  PubMed  Google Scholar 

  42. Guzman JR (2007) Clinical, cellular, and molecular aspects of arterial calcification. J Vasc Surg 45:A57–A63

    Article  PubMed  Google Scholar 

  43. Lehto S, Rönnemaa T, Pyörälä K et al (1996) Risk factors predicting lower extremity amputations in patients with NIDDM. Diabetes Care 19:607–612

    Article  CAS  PubMed  Google Scholar 

  44. Basalyga DM, Simionescu DT, Xiong W et al (2004) Elastin degradation and calcification in an abdominal aorta injury model. Circulation 110:3480–3487

    Article  CAS  PubMed  Google Scholar 

  45. Qin X, Corriere MA, Matrisian LM et al (2006) Matrix metalloproteinase inhibition attenuates aortic calcification. Arterioscler Thromb Vasc Biol 26:1510–1516

    Article  CAS  PubMed  Google Scholar 

  46. Haugen S, Casserly IP, Regensteiner JG et al (2007) Risk assessment in the patient with established peripheral arterial disease. Vasc Med 12:343–350

    Article  PubMed  Google Scholar 

  47. Wilson AM, Kimura E, Harada RK et al (2007) B2-Microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation 116:1396–1403

    Article  CAS  PubMed  Google Scholar 

  48. Busti C, Migliacci R, Falcinelli E et al (2009) Plasma levels of beta(2)-microglobulin, a biomarker of peripheral arterial disease, are not affected by maximal leg exercise in patients with intermittent claudication. Atherosclerosis 203:38–40

    Article  CAS  PubMed  Google Scholar 

  49. Arpegrad J, Ostergren J, de Faire U et al (2008) Cystatine C—a marker of peripheral arterial disease? Atherosclerosis 199:397–401

    Article  Google Scholar 

  50. Lucivero V, Prontera M, Mezzapesa DM et al (2007) Different roles of MMP-2 and–9 after human ischaemic stroke. Neurol Sci 28:165–170

    Article  CAS  PubMed  Google Scholar 

  51. Tayebjee MH, Lip GY, Tan KT et al (2005) Plasma matrix metalloproteinase-9 tissue inhibitor of metalloproteinase-2, and CD40 ligand levels in patients with stable coronary artery disease. Am J Cardiol 96:339–345

    Article  CAS  PubMed  Google Scholar 

  52. Blankenberg S, Rupprecht HJ, Poirier O et al (2003) Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107:1579–1585

    Article  CAS  PubMed  Google Scholar 

  53. Eldrup N, Gronholdt ML, Sillesen H et al (2006) Elevated matrix metalloproteinase-9 associated with stroke or cardiovascular death in patients with carotid stenosis. Circulation 114:1847–1854

    Article  CAS  PubMed  Google Scholar 

  54. Signorelli SS, Malaponte G, Libra M et al (2005) Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. Vasc Med 10:1–6

    Article  PubMed  Google Scholar 

  55. Tayebjee MH, Tan KT, MacFadyen RJ et al (2005) Abnormal circulating levels of metalloprotease 9 and its tissue inhibitor 1 in angiographically proven peripheral arterial disease: relationship to disease severity. J Intern Med 257:110–116

    Article  CAS  PubMed  Google Scholar 

  56. Falcinelli E, Giannini S, Boschetti E, Gresele P (2007) Platelets release active matrix metalloproteinase-2 in vivo in humans at a site of vascular injury. Brit J Haematol 138:221–230

    Article  CAS  Google Scholar 

  57. Gresele P, Catalano M, Giammarresi C et al (1997) Platelet activation markers in patients with peripheral arterial disease—a prospective comparison of different platelet function tests. Thromb Haemost 78:1434–1437

    CAS  PubMed  Google Scholar 

  58. Flex A, Gaetani E, Angelini F et al (2007) Pro-inflammatory genetic profiles in subjects with peripheral arterial occlusive disease and critical limb ischemia. J Intern Med 262:124–130

    Article  CAS  PubMed  Google Scholar 

  59. Adya R, Tan BK, Chen J et al (2008) Nuclear factor-kappaB induction by visfatin in human vascular endothelial cells: its role in MMP-2/9 production and activation. Diabets Care 31:758–760

    Article  CAS  Google Scholar 

  60. Worley JR, Hughes DA, Dozio N et al (2007) Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes. Cardiovasc Diabetol 22:6–21

    Google Scholar 

  61. Chen YH, Wu HL, Chen CK, Huang YH, Yang BC, Wu LW (2003) Angiostatin antagonizes the action of VEGF-A in human endothelial cells via two distinct pathways. Biochem Biophys Res Commun 310:804–810

    Article  CAS  PubMed  Google Scholar 

  62. Hajitou A, Grignet C, Devy L, Berndt S, Blacher S, Deroanne CF, Bajou K, Fong T, Chiang Y, Foidart JM, Noel A (2002) The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. FASEB J 16:1802–1804

    CAS  PubMed  Google Scholar 

  63. Chung AW, Hsiang YN, Matzke LA et al (2006) Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature. Circ Res 99:140–148

    Article  CAS  PubMed  Google Scholar 

  64. Lauhio A, Sorsa T, Srinivas R et al (2008) Urinary matrix metalloproteinase -8, -9, -14 and their regulators (TRY-1, TRY-2, TATI) in patients with diabetic nephropathy. Ann Med 40:312–320

    Article  CAS  PubMed  Google Scholar 

  65. Gonçalves FM, Jacob-Ferreira AL, Gomes VA et al (2009) Increased circulating levels of matrix metalloproteinase (MMP)-8, MMP-9, and pro-inflammatory markers in patients with metabolic syndrome. Clin Chim Acta 403:173–177

    Article  PubMed  Google Scholar 

  66. Li L, Renier G (2008) The oral anti-diabetic agent, gliclazide, inhibits oxidized LDL-mediated LOX-1 expression, metalloproteinase-9 secretion and apoptosis in human aortic endothelial cells. Atherosclerosis [Epub ahead of print]

  67. Forst T, Karagiannis E, Lübben G et al (2008) Pleiotrophic and anti-inflammatory effects of pioglitazone precede the metabolic activity in type 2 diabetic patients with coronary artery disease. Atherosclerosis 197:311–317

    Article  CAS  PubMed  Google Scholar 

  68. Goldstein BJ, Weissman PN, Wooddell MJ et al (2006) Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study. Curr Med Res Opin 22:1715–1723

    Article  CAS  PubMed  Google Scholar 

  69. Lee CS, Kwon YW, Yang HM et al (2009) New mechanism of rosiglitazone to reduce neointimal hyperplasia: activation of glycogen synthase kinase-3beta followed by inhibition of MMP-9. Arterioscler Thromb Vasc Biol 29:472–479

    Article  CAS  PubMed  Google Scholar 

  70. Schieffer B, Bünte C, Witte J et al (2004) Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J Am Coll Cardiol 44:362–368

    Article  CAS  PubMed  Google Scholar 

  71. Yamamoto D, Takai S, Miyazaki M (2008) Inhibitory profiles of captopril on matrix metalloproteinase-9 activity. Eur J Pharmacol 588:277–279

    Article  CAS  PubMed  Google Scholar 

  72. Bellosta S, Via D, Canavesi M et al (1998) HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 18:1671–1678

    CAS  PubMed  Google Scholar 

  73. Crisby M, Nordin-Fredriksson G, Shah PK et al (2001) Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques implications for plaque stabilization. Circulation 103:926–933

    CAS  PubMed  Google Scholar 

  74. Xu Z, Zhao S, Zhou H et al (2004) Atorvastatin lowers plasma matrix metalloproteinase-9 in patients with acute coronary syndrome. Clin Chem 50:750–753

    Article  CAS  PubMed  Google Scholar 

  75. Forrester JS, Libby P (2007) The inflammation hypothesis and its potential relevance to statin therapy. Am J Cardiol 99:732–738

    Article  CAS  PubMed  Google Scholar 

  76. Kenagy RD, Nikkari ST, Welgus HG et al (1994) Heparin inhibits the induction of three matrix metalloproteinases (stromelysin, 92-kD gelatinase, and collagenase) in primate arterial smooth muscle cells. J Clin Invest 93:1987–1993

    Article  CAS  PubMed  Google Scholar 

  77. Grzela T, Brawura-Biskupski-Samaha R et al (2008) Low molecular weight heparin treatment decreases MMP-9 plasma activity in patients with abdominal aortic aneurysm. Eur Vasc Endovasc Surg 35:159–161

    Article  CAS  Google Scholar 

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Acknowledgments

The skilled editorial help of Sara Orsini is gratefully acknowledged. This work was supported in part by a grant from Fondazione Cassa di Risparmio di Perugia (project no. 2007-0130-020) and a grant from the Italian Ministry of Health (REPS-2006-8-334062) to Prof. P. Gresele.

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The authors declare that they have no conflict of interest related to the publication of this manuscript.

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  1. Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via E. dal Pozzo, 06126, Perugia, Italy

    Chiara Busti, Emanuela Falcinelli, Stefania Momi & Paolo Gresele

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  1. Chiara Busti
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  2. Emanuela Falcinelli
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  3. Stefania Momi
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  4. Paolo Gresele
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Correspondence to Paolo Gresele.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s11739-009-0308-6

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Busti, C., Falcinelli, E., Momi, S. et al. Matrix metalloproteinases and peripheral arterial disease. Intern Emerg Med 5, 13–25 (2010). https://doi.org/10.1007/s11739-009-0283-y

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