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Matrix metalloproteinases: not-so-innocent bystanders in heart failure
Richard T. Lee and Peter Libby
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Address for correspondence: Richard T. Lee, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 732-7146; Fax: (617) 264-5139; E-mail: rlee@rics.bwh.harvard.edu.
Find articles by Lee, R. in: JCI | PubMed | Google Scholar
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Address for correspondence: Richard T. Lee, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 732-7146; Fax: (617) 264-5139; E-mail: rlee@rics.bwh.harvard.edu.
Find articles by Libby, P. in: JCI | PubMed | Google Scholar
Published October 1, 2000 - More info
J Clin Invest. 2000;106(7):827–828. https://doi.org/10.1172/JCI11263.
© 2000 The American Society for Clinical Investigation
For decades, the classic teaching of the pathophysiology of heart failure has focused, quite reasonably, on the inside of the cardiac myocyte. The dynamic states of the contractile proteins and exquisite controls of intracellular calcium movements coordinate myocardial contraction and relaxation and appeared to be prime suspects in all forms of systolic and diastolic dysfunction. Furthermore, molecular genetics has implicated mutations in the cytoskeleton as important causes of cardiomyopathy in both mice and humans (1). In contrast, the extracellular matrix (ECM) seemed to serve only a passive role, providing a relatively static external structure whose rates of metabolic turnover appeared much too slow to influence cardiac contractility or hypertrophy directly. Cardiac myocytes did their work on the inside, while the matrix seemed to just hang on for the ride.
It is not surprising, then, that the potential role in heart failure has only recently emerged for the matrix metalloproteinases (MMPs), a family of enzymes with broad roles in ECM metabolism. While processes such as inflammatory destruction of articular cartilage matrix or invasion of metastatic cancer cells clearly depend upon active ECM degradation, the role of ECM degradation in myocardial hypertrophy and dysfunction is less intuitive. MMPs are overexpressed in many forms of myocardial dysfunction in both experimental models and human diseases (2), but MMP overexpression is ubiquitous in changing or remodeling tissues. Thus, the enzymes could easily be taken for innocent bystanders in heart failure.
For several reasons, MMPs must now be regarded as viable suspects in heart failure. First, the ECM is both physically and biochemically in close communication with the cytoskeleton. The general concept that matrix molecules can provide powerful “outside-in” cellular signals through ECM receptors such as β1 integrins applies to the cardiac myocyte (3). Furthermore, molecular defects in the dystrophin-dystroglycan-laminin complex, which links the cytoskeleton with the ECM, have been shown to cause cardiomyopathy in both humans and animals (4). In addition, studies of MMP inhibitors in different animal models (5, 6) as well as in transgenic mice with deletion of MMP-9 (7) demonstrate that MMPs can profoundly influence the process of cardiac dilation, a central feature of heart failure progression.
In this issue of the JCI, Kim et al. (8) further implicate MMPs in heart failure by providing direct evidence that disruption of the ECM by MMP-1 can cause cardiac hypertrophy and dysfunction. By overexpressing human MMP-1, a collagenase that initiates degradation of fibrillar collagen, in cardiac ventricles of mice, they have developed a unique model for demonstrating the importance of the collagen scaffold of the myocardium. By 6 months of age, these animals develop myocyte hypertrophy, and by 12 months they develop both systolic and diastolic dysfunction. Their experimental model is particularly interesting because mice and other rodents carry no endogenous MMP-1 gene; another metalloproteinase, MMP-13, appears to serve as a fibrillar collagenase in these species. Thus, the experiment was not confounded by compensatory changes in expression of a mouse MMP-1 homologue.
This study is also of interest for what it does not show. Deletion of MMPs in genetically engineered mice has resulted in predominantly mild or normal phenotypes, suggesting that some members of the family can substitute for others during development. In contrast, challenge of these models with pathophysiologic stimuli has elicited important roles for individual MMP enzymes (9). Because Kim et al. used the α myosin heavy chain promoter, which targets expression to the cardiac myocyte predominantly postnatally, their model does not preclude an important role for an intact collagen scaffold during normal cardiac morphogenesis.
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