3. 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
4. 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
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
6. 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
7. 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
8. 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.
9. 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?
11. 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
References
12. 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.
8. 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.
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