Matrix metalloproteinases: are they antiatherogenic but proaneurysmal?

Abstract

HomeCirculation ResearchVol. 90, No. 8Matrix Metalloproteinases Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMatrix MetalloproteinasesAre They Antiatherogenic but Proaneurysmal? Michelle P. Bendeck Michelle P. BendeckMichelle P. Bendeck From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Search for more papers by this author Originally published3 May 2002https://doi.org/10.1161/01.RES.0000018141.73992.41Circulation Research. 2002;90:836–837The matrix metalloproteinases (MMPs) are a family of enzymes (25 identified to date) that have in common the ability to degrade many molecules of the extracellular matrix. MMP activity can be inhibited by the endogenous tissue inhibitors of metalloproteinases (TIMPs 1 through 4), and the net proteolytic activity within a tissue is a function of the balance of MMPs/TIMPs.1 Numerous studies have shown that MMPs and TIMPs are expressed during vascular remodeling in the pathological conditions of atherosclerosis, restenosis, and aneurysm formation.2 Despite this burgeoning knowledge, we are still hampered by an incomplete understanding of the scope and the consequences of MMP/TIMP involvement in the pathogenesis of vascular disease.In atherosclerosis and restenosis, MMPs are produced by the major cell types inhabiting the plaque, vascular smooth muscle cells (SMCs), and leukocytes of the monocyte/macrophage and lymphocytic lineages. MMP-1, -2, -3, -9, -12, and -13 have been detected in plaques, along with the TIMP-1, -2, and -4.2 MMPs produced by SMCs clear a path for migration from media to intima by digesting the extracellular matrix, and SMC migration can be inhibited by administration of nonselective MMP inhibitors3–5 or transfection of the genes for TIMP-1 or TIMP-2 into the injured vessel wall.6,7 Macrophages produce abundant amounts of MMPs, which are used to invade through the endothelium and into the atherosclerotic plaque.8 MMPs are colocalized with macrophages in the core and shoulders of established plaques, areas that are very susceptible to the complications of erosion and rupture.9 MMPs are also expressed by inflammatory cells found in abdominal aortic aneurysms,10 and experimental studies using rat and mouse models point to a causal role for the MMPs in the pathogenesis of aneurysm.11,12A great deal of effort in vascular biology has centered on the hypothesis that inhibiting MMP activity will reduce plaque volume by inhibiting the migration of SMCs and macrophages into the plaque and prevent the later complications of plaque rupture and aneurysm formation. However, the mechanisms of MMP action in complex models of atherosclerosis are largely unknown. With the advent of transgenic technology, better models of atherosclerosis have been developed, including the cholesterol-fed ApoE-null mouse, which is characterized by elevated circulating lipoproteins, and the development of lipid-rich plaques containing inflammatory macrophages and lymphocytes.13In an article published in this issue of Circulation Research, Silence et al14 have uncovered dual roles of MMPs in the ApoE-null mouse model of atherosclerosis. Surprisingly, they found that deletion of the TIMP-1 gene resulted in reduction of plaque size in the ApoE-null mouse. TIMP-1 inhibits the activity of many MMPs, including the collagenases, gelatinases, and stromelysins. In the absence of the TIMP-1 gene, there was an increase in the number of macrophages present in aortic intimal lesions. The authors postulate that increased MMP activity (predominantly MMP-2), which colocalized with the macrophages, resulted in collagen degradation, thereby reducing plaque size. The reduction in plaque size was evident despite increased lipid accumulation in the lesions of the ApoE-null:TIMP-1-null mice. Unfortunately, the potential for aneurysm formation was substantially elevated in these mice, as evidenced by an increase in the frequency of disruptions in the internal elastic lamina.The results presented here seemingly contradict a central dogma in atherosclerosis—that increased MMP activity leads to the formation of a thicker neointima. However, we must remember that most of the earlier studies with MMP inhibitors used experimental models where SMC migration was the main, if not the only, determinant of intimal lesion formation. By contrast, a growing body of experimental evidence from murine atherosclerosis models supports the postulate that increased macrophage-derived MMP activity may limit plaque progression. For example, plaque size and collagen content were greater in mice with double knockout of the MMP-3 and ApoE genes, compared to ApoE-null littermate controls.15 Consistent with this, plaque size, lipid deposition, and collagen content were reduced in ApoE-null mice that overexpressed MMP-1 in the macrophages.16 Taken together with results from the present study, this suggests that the activity of several plaque MMPs may actually be antiatherogenic. In this light, it is interesting to note that polymorphisms in the human MMP-3 promoter leading to decreased expression of this gene have been correlated with an increased incidence of atherosclerosis.17 Further work will be necessary to determine the full spectrum of anti- or proatherogenic activities of the many MMPs that are expressed in atherosclerosis. Another caveat is that the previous studies using knockout mice address only plaque progression. By contrast, increasing circulating TIMP-1 levels in the ApoE-null mouse induced the regression of pre-established lesions.18 Thus, the effects of altering the balance of MMPs/TIMPs may differ during the time course of lesion development.Although the reduction in plaque size seen in the absence of TIMP-1 is potentially beneficial, deletion of TIMP-1 leads to increased degradation of the aortic elastic lamellae and thus may predispose to aneurysmal dilation and rupture. This is probably due to the increase in the amounts and the diversity of the MMPs produced by macrophages and/or to increased MMP activation by reactive oxygen species, nitric oxide, and peroxynitrite formation.19 In this context, it is interesting to speculate that aneurysm formation may be a case of MMP-mediated outward vessel remodeling gone bad.20 In the future, it will be important to investigate the potential for plaque rupture in the ApoE-null:TIMP-1-null mouse model. Rosenfeld et al21 have reported a significant incidence of intraplaque hemorrhage and plaque rupture at very late times during lesion development in the ApoE-null mouse model. In the absence of TIMP-1, the increased clearance of collagen may accelerate the destabilization of the atherosclerotic plaque, leaving it vulnerable to rupture.Finally, it is important to remember that MMPs and TIMPs have functions beyond their roles in matrix degradation. For example, TIMP-1 is a growth factor for several cell types.1 In addition, MMPs degrade components of the extracellular matrix that stimulate cell growth and migration, such as collagen and osteopontin.23–25 MMPs also disrupt cell-cell interactions by cleaving cadherins or disrupting matrix-integrin associations, leading to apoptosis.1 Any of these mechanisms could be pertinent to atheroma or aneurysm formation, because they lead to a reduction in cell number.In conclusion, the data presented in this interesting study highlights the importance of assessing all the potential mechanisms of MMP/TIMP action in the most appropriate experimental models. Clearly the use of transgenic mouse models is extremely informative, but also very complicated. We must take great care to interpret the data in terms of the cell types present in human atherosclerosis, available knowledge of the diversity of MMP/TIMP functions, and the time course of expression and activity of these enzymes. In this way, we can design selective therapies to be administered at the appropriate time and location to prevent the progression and complications of atherosclerosis.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Dr Michelle P. Bendeck, Dept of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 1 King’s College Cir, Room 6217A, Toronto, Ontario M5S 1A8, Canada. E-mail [email protected] utoronto.ca References 1 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463–516.CrossrefMedlineGoogle Scholar2 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002; 90: 251–262.LinkGoogle Scholar3 Bendeck MP, Irvin C, Reidy MA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res. 1996; 78: 38–43.CrossrefMedlineGoogle Scholar4 Zempo N, Koyama N, Kenagy RD, Lea HJ, Clowes A. 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.CrossrefMedlineGoogle Scholar5 Bendeck MP, Conte M, Zhang M, Nili N, Strauss BH, Farwell SM. Doxycycline modulates smooth muscle cell growth, migration and matrix remodeling after arterial injury. Am J Pathol. 2002; 160: 1089–1095.CrossrefMedlineGoogle Scholar6 Forough R, Koyama N, Hasenstab D, Lea H, Clowes M, Nikkari ST, Clowes AW. Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ Res. 1996; 79: 812–820.CrossrefMedlineGoogle Scholar7 George SJ, Baker AH, Angelini GD, Newby AC. Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins. Gene Ther. 1998; 5: 1552–1560.CrossrefMedlineGoogle Scholar8 Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci U S A. 1995; 92: 402–406.CrossrefMedlineGoogle Scholar9 Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaque. J Clin Invest. 1994; 94: 2493–2503.CrossrefMedlineGoogle Scholar10 Thompson RW, Parks WC. Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann N Y Acad Sci. 1996; 800: 157–174.CrossrefMedlineGoogle Scholar11 Allaire E, Forough R, Clowes M, Starcher B, Clowes AW. Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest. 1998; 102: 1413–1420.CrossrefMedlineGoogle Scholar12 Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest. 2000; 105: 1641–1649.CrossrefMedlineGoogle Scholar13 Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E–deficient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.CrossrefMedlineGoogle Scholar14 Silence J, Collen D. Lijnen HR. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) gene. Circ Res. 2002; 90: 897–903.LinkGoogle Scholar15 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.CrossrefMedlineGoogle Scholar16 Lemaitre V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, D’Armiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest. 2001; 107: 1227–1234.CrossrefMedlineGoogle Scholar17 Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. 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.CrossrefMedlineGoogle Scholar18 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.CrossrefMedlineGoogle Scholar19 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.CrossrefMedlineGoogle Scholar20 Pasterkamp G, de Kleijn DP, Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovasc Res. 2000; 45: 843–852.CrossrefMedlineGoogle Scholar21 Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000; 20: 2587–2592.CrossrefMedlineGoogle Scholar22 Deleted in proof.Google Scholar23 Hou G, Mulholland D, Gronska MA, Bendeck MP. Type VIII collagen stimulates smooth muscle cell migration and matrix metalloproteinase synthesis after arterial injury. Am J Pathol. 2000; 156: 467–476.CrossrefMedlineGoogle Scholar24 Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res. 1994; 74: 214–224.CrossrefMedlineGoogle Scholar25 Rocnik EF, Chan BMC, Pickering JG. Evidence for a role of collagen synthesis in arterial smooth muscle cell migration. J Clin Invest. 1998; 101: 1889–1898.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mountain D, Kirkpatrick S, Arnold J, Buckley M, McNally M, Stevens S, Freeman M and Grandas O (2019) The Efficacy of Systemic Doxycycline Administration as an Inhibitor of Intimal Hyperplasia after Balloon Angioplasty Arterial Injury, Annals of Vascular Surgery, 10.1016/j.avsg.2018.11.005, 57, (201-209), Online publication date: 1-May-2019. Ahmad M, Kiani I, Ammar K, Ahmad M, Khandheria B, Paterick T, Jain R and Tajik A (2017) Ascending Aortic Aneurysm Is an Inherited Disease, Cardiology in Review, 10.1097/CRD.0000000000000146, 25:6, (268-278), Online publication date: 1-Nov-2017. Mountain D, Freeman M, Kirkpatrick S, Cook R, Chalk J, Stevens S, Goldman M and Grandas O (2013) Effect of Hormone Replacement Therapy in Matrix Metalloproteinase Expression and Intimal Hyperplasia Development After Vascular Injury, Annals of Vascular Surgery, 10.1016/j.avsg.2012.05.010, 27:3, (337-345), Online publication date: 1-Apr-2013. Pradhan-Palikhe P, Vikatmaa P, Lajunen T, Palikhe A, Lepäntalo M, Tervahartiala T, Salo T, Saikku P, Leinonen M, Pussinen P and Sorsa T (2010) Elevated MMP-8 and Decreased Myeloperoxidase Concentrations Associate Significantly with the Risk for Peripheral Atherosclerosis Disease and Abdominal Aortic Aneurysm1, Scandinavian Journal of Immunology, 10.1111/j.1365-3083.2010.02418.x, 72:2, (150-157) Liu X, Manzano G, Lovett D and Kim H (2010) Role of AP-1 and RE-1 binding sites in matrix metalloproteinase-2 transcriptional regulation in skeletal muscle atrophy, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2010.04.067, 396:2, (219-223), Online publication date: 1-May-2010. Elefteriades J and Farkas E (2010) Thoracic Aortic Aneurysm, Journal of the American College of Cardiology, 10.1016/j.jacc.2009.08.084, 55:9, (841-857), Online publication date: 1-Mar-2010. Liu X, Lee D, Skittone L, Natsuhara K and Kim H (2009) Role of gelatinases in disuse-induced skeletal muscle atrophy, Muscle & Nerve, 10.1002/mus.21463, 41:2, (174-178), Online publication date: 1-Feb-2010. Elefteriades J (2008) Thoracic Aortic Aneurysm: Reading the Enemy's Playbook, Current Problems in Cardiology, 10.1016/j.cpcardiol.2008.01.004, 33:5, (203-277), Online publication date: 1-May-2008. Skittone L, Liu X, Tseng A and Kim H (2008) Matrix metalloproteinase-2 expression and promoter/enhancer activity in skeletal muscle atrophy, Journal of Orthopaedic Research, 10.1002/jor.20513, 26:3, (357-363), Online publication date: 1-Mar-2008. Meng Q, Jamal W, Hart S and McEwan J (2006) Application to Vascular Adventitia of a Nonviral Vector for TIMP-1 Gene Therapy to Prevent Intimal Hyperplasia, Human Gene Therapy, 10.1089/hum.2006.17.717, 17:7, (717-727), Online publication date: 1-Jul-2006. Meng Q, Jamal W, Hart S and McEwan J (2006) Application to Vascular Adventitia of a Nonviral Vector for TIMP-1 Gene Therapy to Prevent Intimal Hyperplasia, Human Gene Therapy, 10.1089/hum.2006.17.ft-219, 0:0, (060801084750029) Sinha I, Hannawa K, Ailawadi G, Woodrum D, Ford J, Henke P, Stanley J, Eagleton M and Upchurch G (2006) The Nitric Oxide Donor DETA-NONOate Decreases Matrix Metalloproteinase-9 Expression and Activity in Rat Aortic Smooth Muscle and Abdominal Aortic Explants, Annals of Vascular Surgery, 10.1007/s10016-005-9429-1, 20:1, (92-98), Online publication date: 1-Jan-2006. Achneck H, Modi B, Shaw C, Rizzo J, Albornoz G, Fusco D and Elefteriades J (2005) Ascending Thoracic Aneurysms Are Associated With Decreased Systemic Atherosclerosis, Chest, 10.1378/chest.128.3.1580, 128:3, (1580-1586), Online publication date: 1-Sep-2005. Hornebeck W, Bellon G and Emonard H (2005) Fibronectin type II (FnII)-like modules regulate gelatinase A activity, Pathologie Biologie, 10.1016/j.patbio.2004.12.015, 53:7, (405-410), Online publication date: 1-Sep-2005. Guignabert C, Taysse L, Calvet J, Planus E, Delamanche S, Galiacy S and d'Ortho M (2005) Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00475.2004, 289:1, (L67-L74), Online publication date: 1-Jul-2005. Chen J, Han Y, Lin C, Zhen Y, Song X, Teng S, Chen C, Chen Y, Zhang Y and Hui R (2005) PDGF-D contributes to neointimal hyperplasia in rat model of vessel injury, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2005.02.062, 329:3, (976-983), Online publication date: 1-Apr-2005. Ikonomidis J, Gibson W, Butler J, McClister D, Sweterlitsch S, Thompson R, Mukherjee R and Spinale F (2004) Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms, Circulation, 110:11_suppl_1, (II-268-II-273), Online publication date: 14-Sep-2004.Cozen A, Moriwaki H, Kremen M, DeYoung M, Dichek H, Slezicki K, Young S, Véniant M and Dichek D (2004) Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death, Circulation, 109:17, (2129-2135), Online publication date: 4-May-2004. Rackley C (2004) New Clinical Markers Predictive of Cardiovascular Disease, Cardiology in Review, 10.1097/01.crd.0000126083.86717.5b, 12:3, (151-157), Online publication date: 1-May-2004. Smeglin A and Frishman W (2004) Elastinolytic Matrix Metalloproteinases and Their Inhibitors as Therapeutic Targets in Atherosclerotic Plaque Instability, Cardiology in Review, 10.1097/01.crd.0000105000.46909.81, 12:3, (141-150), Online publication date: 1-May-2004. Rödel J, Prochnau D, Prager K, Pentcheva E, Hartmann M and Straube E (2003) Increased production of matrix metalloproteinases 1 and 3 by smooth muscle cells upon infection with Chlamydia pneumoniae , FEMS Immunology & Medical Microbiology, 10.1016/S0928-8244(03)00126-3, 38:2, (159-164), Online publication date: 1-Sep-2003. Wu M, Chiou H, Ho I, Chen C and Lee T (2003) Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects., Environmental Health Perspectives, 10.1289/ehp.6396, 111:11, (1429-1438), Online publication date: 1-Aug-2003. Medley T, Kingwell B, Gatzka C, Pillay P and Cole T (2003) Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression, Circulation Research, 92:11, (1254-1261), Online publication date: 13-Jun-2003. May 3, 2002Vol 90, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000018141.73992.41PMID: 11988481 Originally publishedMay 3, 2002 Keywordsvascular remodelingatherosclerosismatrix metalloproteinasesaneurysmPDF download Advertisement