This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bendeck, M. P. Search for Related Content PubMed PubMed Citation Articles by Bendeck, M. P. Related Collections Animal models of human disease Pathophysiology

(Circulation Research. 2002;90:836.)
© 2002 American Heart Association, Inc.

Editorials

Matrix Metalloproteinases

Are They Antiatherogenic but Proaneurysmal?

Michelle P. Bendeck

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.

Correspondence 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 michelle.bendeck@ utoronto.ca

Key Words: matrix metalloproteinases • vascular remodeling • aneurysm • atherosclerosis

The 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 inhibitors^3–5 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.^11,12

A 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.¹³

In 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.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463–516.[CrossRef][Medline] [Order article via Infotrieve]
2. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002; 90: 251–262.[Abstract/Free Full Text]
3. 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.[Abstract/Free Full Text]
4. 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.[Abstract/Free Full Text]
5. 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.[Abstract/Free Full Text]
6. 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.[Abstract/Free Full Text]
7. 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.[CrossRef][Medline] [Order article via Infotrieve]
8. 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.[Abstract/Free Full Text]
9. 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.[Medline] [Order article via Infotrieve]
10. Thompson RW, Parks WC. Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann N Y Acad Sci. 1996; 800: 157–174.[Abstract]
11. 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.[Medline] [Order article via Infotrieve]
12. 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.[Medline] [Order article via Infotrieve]
13. 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.[CrossRef][Medline] [Order article via Infotrieve]
14. 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.[Abstract/Free Full Text]
15. 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.[Abstract/Free Full Text]
16. 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.[Medline] [Order article via Infotrieve]
17. 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.[Abstract/Free Full Text]
18. 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.[Abstract/Free Full Text]
19. 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.[Medline] [Order article via Infotrieve]
20. 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.[Abstract/Free Full Text]
21. 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.[Abstract/Free Full Text]
22. Deleted in proof.
23. 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.[Abstract/Free Full Text]
24. 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.[Abstract/Free Full Text]
25. 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.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				T. Shimokawa, K. Horiuchi, N. Ozawa, K. Fumimoto, S. Manabe, T. Tobaru, and S. Takanashi Outcome of surgical treatment in patients with acute type B aortic dissection. Ann. Thorac. Surg., July 1, 2008; 86(1): 103 - 107. [Abstract] [Full Text] [PDF]

				T. Shimokawa, S. Takanashi, N. Ozawa, and T. Itoh Management of intraoperative malperfusion syndrome using femoral artery cannulation for repair of acute type A aortic dissection. Ann. Thorac. Surg., May 1, 2008; 85(5): 1619 - 1624. [Abstract] [Full Text] [PDF]

				H. Achneck, B. Modi, C. Shaw, J. Rizzo, G. Albornoz, D. Fusco, and J. Elefteriades Ascending Thoracic Aneurysms Are Associated With Decreased Systemic Atherosclerosis Chest, September 1, 2005; 128(3): 1580 - 1586. [Abstract] [Full Text] [PDF]

				C. Guignabert, L. Taysse, J.-H. Calvet, E. Planus, S. Delamanche, S. Galiacy, and M.-P. d'Ortho Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L67 - L74. [Abstract] [Full Text] [PDF]

				D. S. Fusco, R. K. Shaw, M. Tranquilli, G. S. Kopf, and J. A. Elefteriades Femoral Cannulation is Safe for Type A Dissection Repair Ann. Thorac. Surg., October 1, 2004; 78(4): 1285 - 1289. [Abstract] [Full Text] [PDF]

				J. S. Ikonomidis, W. C. Gibson, J. E. Butler, D. M. McClister, S. E. Sweterlitsch, R. P. Thompson, R. Mukherjee, and F. G. Spinale Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms Circulation, September 14, 2004; 110(11_suppl_1): II-268 - II-273. [Abstract] [Full Text] [PDF]

				A. E. Cozen, H. Moriwaki, M. Kremen, M. B. DeYoung, H. L. Dichek, K. I. Slezicki, S. G. Young, M. Veniant, and D. A. Dichek Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death Circulation, May 4, 2004; 109(17): 2129 - 2135. [Abstract] [Full Text] [PDF]

				T. L. Medley, B. A. Kingwell, C. D. Gatzka, P. Pillay, and T. J. Cole Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression Circ. Res., June 13, 2003; 92(11): 1254 - 1261. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bendeck, M. P. Search for Related Content PubMed PubMed Citation Articles by Bendeck, M. P. Related Collections Animal models of human disease Pathophysiology