A clear cause-effect relationship between matrix metalloproteinase (MMP) induction/activation and the myocardial remodeling process following myocardial infarction (Ml) has been established. However, it is unlikely that MMP expression is a uniform and global process post-MI, but rather one that is tightly orchestrated with respect to MMP type, location and time. The central hypothesis of this continuing project is that MMP induction/activation following Ml is type, region and time dependent;and this process can be visualized, quantified and targeted in-vivo. Past studies have used myocardial extracts to determine relative MMP abundance post-MI but this approach does not allow for spatial/ temporal assessment, removes MMPs from the environment where endogenous inhibitors of MMPs (TIMPs) are operative, and cannot be advanced to relevant clinical application. Accordingly, this project will accomplish the following aims: (1) Demonstrate that the induction of MMP types post-MI is region and time dependent through the use of novel transgenic reporter constructs and demonstrate that this induction can be modified by targeting upstream signaling events. (2) Map the in-vivo spatial and temporal induction in MMP activation in mice post- MI and demonstrate that net proteolytic activity imaged in-vivo is sensitive to genetic/pharmacological modulation. (3) Demonstrate that a unique MMP type, MT1-MMP plays a critical role in post-MI remodeling, that MT1-MMP activity can be quantified within the myocardial interstitium post-MI, and can be visualized in- vivo. This project will identify upstream targets for in-vivo MMP induction and methods to assess MMP activation within the remodeling myocardium and thereby hold diagnostic/prognostic and therapeutic potential for patients that are at increased risk for adverse remodeling and heart failure post-MI. Relevance to public health: One of the most common causes of death and disability in this country is from a heart attack;damage to the heart muscle. Following a heart attack, it is now clear that enzymes are made that continue to chew away at the heart muscle and eventually cause the heart to fail. This study will develop methods to measure and block these enzymes following a heart attack. These results will help develop new tests and treatments for patients suffering from heart failure after a heart attack.
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