Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?
Departments of Pathology, Cardiovascular Research Institute
Maastricht, University of Maastricht, The Netherlands.
Increased activity of matrix metalloproteinases (MMPs) has
been implicated in numerous disease processes, including tumor
growth and metastasis, arthritis, and periodontal disease.
It is now becoming increasingly clear that extracellular matrix
degradation by MMPs is also involved in the pathogenesis of
cardiovascular disease, including atherosclerosis, restenosis,
dilated cardiomyopathy, and myocardial infarction. Administration
of synthetic MMP inhibitors in experimental animal models of
these cardiovascular diseases significantly inhibits the progression
of, respectively, atherosclerotic lesion formation, neointima
formation, left ventricular remodeling, pump dysfunction, and
infarct healing. This review focuses on the role of MMPs in
cardiovascular disease, in particular myocardial infarction
and the subsequent progression to heart failure. MMPs, which
are present in the myocardium and capable of degrading all
the matrix components of the heart, are the driving force behind
myocardial matrix remodeling. The recent finding that acute
pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates
left ventricular dilatation in the infarcted mouse heart led
to the proposal that MMP inhibitors could be used as a potential
therapy for patients at risk for the development of heart failure
after myocardial infarction. Although these promising results
encourage the design of clinical trials with MMP inhibitors,
there are still several unresolved issues. This review describes
the biology of MMPs and discusses new insights into the role
of MMPs in several cardiovascular diseases. Attention will
be paid to the central role of the plasminogen system as an
important activator of MMPs in the remodeling process after
myocardial infarction. Finally, we speculate on the use of
MMP inhibitors as potential therapy for heart failure.
