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Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Matrix metalloproteinase inhibition and the prevention of heart failure
1Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, MA, USA. rlee@rics.bwh.harvard.edu
Abstract:
Matrix metalloproteinases (MMPs) are members of a large family of enzymes that can degrade extracellular matrix as well as other molecules. MMPs participate in a broad variety of normal and pathologic states, and recent evidence implicates the MMP family as potential mediators of cardiac dilation and progression to heart failure. This evidence is based on several lines of investigation. First, members of the MMP family are overexpressed in the myocardium in both experimental and human myocardial injury, infarction, and dilation. Second, overexpression of at least one MMP (MMP-1) in the hearts of transgenic mice can cause cardiac hypertrophy, dilation, and systolic dysfunction. Third, studies from multiple laboratories with different experimental models indicate that inhibition of MMPs through small molecules or gene transfer of endogenous inhibitors favorably affects cardiac remodeling. Fourth, targeted deletion of MMP genes in mice attenuates cardiac remodeling. These compelling results appear to fulfill Koch's Postulates as they may be applied to a non-infectious mediator of a disease, and thus current evidence supports MMP inhibition as a promising strategy for preventing heart failure. However, the crucial question of whether MMP inhibition benefits long-term left ventricular function and survival should be answered.
Insights
Matrix metalloproteinases (MMPs) are implicated in heart failure progression. Inhibiting MMPs shows promise in preventing cardiac remodeling and may be a viable strategy for heart failure prevention.
Area of Science:
- Cardiovascular biology
- Enzymology
- Molecular medicine
Background:
- Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix degradation.
- MMPs play roles in both normal physiological processes and various pathological conditions.
- Emerging evidence suggests MMPs are key mediators in the development and progression of cardiac dilation and heart failure.
Purpose of the Study:
- To review the evidence implicating matrix metalloproteinases (MMPs) in the pathogenesis of cardiac dilation and heart failure.
- To assess the potential of MMP inhibition as a therapeutic strategy for preventing heart failure.
Main Methods:
- Review of experimental and human studies on MMPs in myocardial injury, infarction, and dilation.
- Analysis of data from transgenic mice overexpressing MMPs and gene-deleted mice.
- Evaluation of studies using small molecule inhibitors or gene transfer to inhibit MMPs.
- Assessment of evidence in the context of Koch's Postulates for non-infectious disease mediators.
Main Results:
- MMP family members are upregulated in the myocardium during injury, infarction, and dilation.
- Overexpression of MMP-1 in mice leads to cardiac hypertrophy, dilation, and dysfunction.
- Inhibition of MMPs, via small molecules or gene transfer, improves cardiac remodeling in various models.
- Targeted deletion of MMP genes in mice attenuates cardiac remodeling.
Conclusions:
- Current evidence strongly supports MMPs as mediators of cardiac remodeling and progression to heart failure.
- MMP inhibition represents a promising therapeutic strategy for preventing heart failure.
- Further research is needed to determine the long-term benefits of MMP inhibition on left ventricular function and survival.
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