Editorial Slides VP Watch, January 30, 2002, Volume 2, Issue 4

MMPs: The Dirty Dozen!

MMP 1 Collagenase MMP 11 Stromelysin-3

MMP 2 Gelatinase A MMP 12 Macrophage Metalloelastase

MMP 3 Stromelysin-1 MMP 13 Collagenase-3

MMP 7 Matrilysin MMP 14 MT-MMP-1

MMP 8 Neutrophil Collagenase

MMP 15 MT-MMP-2

MMP 9 Gelatinase B MMP 16 MT-MMP-3

MMP 10 Stromelysin-2 MMP 17 MT-MMP-4

MMP 20 Enamelysin

Adapted from R&D SYSTEMSwww.rndsystems.com

The MMPs constitute a family of endopeptidases that need zinc and calcium for their function.1

MMPs are enzymes that participate in the physiological and pathological remodeling of extra-cellular matrix. 2

The ability of certain MMPs, such as MMP-2, MMP-3, MMP-9, and MMP-12, to hydrolyze elastin is of particular importance in terms of their effects on the vasculature. 1

Several studies have shown the presence of matrix metalloproteinases 1, 2, 3, 9 and 12 in atherosclerotic plaque development and rupture.3,6

Recently MMP-8 was shown co-localized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture. 5

MMPs have the ability to react with specific tissue inhibitors of metalloproteinases (TIMPs) to form enzymatically inactive complexes. 1

Herman, Libby, and colleagues found that the serine proteinase tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. 4

Sukhova, Libby, and colleagues found that the presence of cathepsins K and S at sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for non-MMP proteinases in vessel wall remodeling and plaque rupture. 7

Pyo and colleagues showed that targeted gene disruption of matrix etalloproteinase-9(gelatinase B) suppresses development of experimental abdominal aortic aneurysms.12

Libby and others found that statins can reduce MMP expression in atheroma and that cell-permeant statins can increase SMC number and collagen gene expression in vivo. 9

As highlighted in this week VP Watch, Carrell and colleagues found that both abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) walls express similar levels of a wide range of MMPs, including cell membrane–bound MT-MMPs. 11

They determined that stromelysin-1 (MMP-3) and tissue inhibitors of metalloproteinases-3 were over-expressed in the AAA samples and may be involved in aneurysm pathogenesis. 11

Conclusion:

I. MMP3 and its inhibitor (TIMP-3) are over expressed in atherosclerotic aneurysmal aorta.

II. Inhibition of MMP3 might be a potential therapeutic approach for treatment of atherosclerotic aneurysmal disorders. Similarly it may offer therapeutic opportunities for plaque stabilization and prevention of rupture.

Questions:I. Having dozens of MMPs involved in atherosclerotic

plaque development and/or complication, the question is how effectively inhibition of one MMP may prevent plaque rupture?

II. Having non-MMPs proteases reported as significant player in atherosclerotic plaque, one would want to know which one to target, MMPs or non-MMPs?

III. Knowing the unwanted results of MMP inhibitors in cancer trials, is there any hope for MMP trials in cardiovascular and vulnerable plaque field?

Suggestion:VP.org Editorial Suggestion:

- Please email your thoughts to:

Discussion-Group@VP.org or DG@VP.org

1. Victor J. Ferrans; New Insights Into the World of Matrix Metalloproteinases; Circulation 2002 105: 405 - 407.

2. aaaGalis ZS. Metalloproteases in remodeling of vascular extracellular matrix. Fibrin Proteol. 1999;13:54–63.

3. 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 Jun 23;97(24):2445-53.

4. Herman MP, Sukhova GK, Kisiel W, Foster D, Kehry MR, Libby P, Schonbeck U.Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. J Clin Invest. 2001 May;107(9):1117-26.

5. aHerman MP, Sukhova GK, Libby P, Gerdes N, Tang N, Horton DB, Kilbride M, Breitbart RE, Chun M, Schonbeck U.Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling.Circulation. 2001 Oct 16;104(16):1899-904.

6. aaaRekhter MD, Hicks GW, Brammer DW, Hallak H, Kindt E, Chen J, Rosebury WS, Anderson MK, Kuipers PJ, Ryan MJ. Hypercholesterolemia causes mechanical weakening of rabbit atheroma: local collagen loss as a prerequisite of plaque rupture. Circ Res. 2000;86:101–108.

7. Galina K. Sukhova, Guo-Ping Shi, Daniel I. Simon, Harold A. Chapman, and Peter LibbyExpression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998 Aug 1;102(3):576-83.

References

8. Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P. An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro. Circulation. 2001 Jan 16;103(2):276-283.

9. Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits

Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto

Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, and Masanori Aikawa Circulation 2001 103: 993 - 999.

10. Loftus IM, Naylor AR, Bell PR, Thompson MM; Related Articles Plasma MMP-9 - a marker of carotid plaque instability.

Eur J Vasc Endovasc Surg. 2001 Jan;21(1):17-21.

11. Tom W.G. Carrell, Kevin G. Burnand, Graham M.A. Wells, John M. Clements, and Alberto Smith 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.

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 Jun;105(11):1641-9.

References