This is an A2 resubmission of a renewal application to study left ventricular remodeling following myocardial infarction (MI). MI, even with current therapeutic strategies, remains a leading cause of heart failure. The identification of events that stimulate adverse remodeling of the left ventricle (LV) post-MI may provide therapeutic targets to prevent, slow, or reverse the progression to heart failure. Post-MI, extracellular matrix (ECM) turnover is a driving event in LV remodeling, and there is a well- established association between the inflammatory response and ECM turnover. An initial analysis of matrix metalloproteinase-9 (MMP-9) functions suggests that this particular MMP predominantly influences remodeling by altering the macrophage response, as MMP-9 null mice show impaired macrophage influx into the LV post- MI. MMP-9 has been shown to cleave ECM to generate bioactive peptides and to activate transforming growth factor b (TGFb), which potentially places MMP-9 downstream of the macrophage and upstream of key events that involve the cardiac fibroblast. The long-term goals of this project, accordingly, are to understand the roles of macrophages and macrophage-derived MMP-9 in the LV response to MI. This proposal will focus on elucidating macrophage and MMP-9 driven mechanisms to critically test the hypothesis that macrophages modulate the LV response to MI through MMP-9 effects on ECM substrates and transforming growth factor-b. Using a unique cell specific transgenic mouse model that overexpresses human MMP-9 only in macrophages and specific MMP-9 and TGFb interventions, we will determine the MMP-9 mediated events that most influence LV remodeling. To test our central hypothesis, we will 1) determine whether macrophage levels and activation status regulate fibroblast activation and LV remodeling;2) determine whether MMP-9 and TGFb regulate macrophage phenotype, fibroblast activation, and LV remodeling;and 3) determine whether bioactive ECM peptides generated by MMP-9 regulate LV remodeling post-MI through macrophage and fibroblast activation. We will use a multi-discipline approach that integrates physiology, cell biology, biochemistry, mass spectrometry, and histological approaches to unveil mechanisms and quantify the LV remodeling process as a function of macrophage activation status and MMP-9 levels. This proposal is innovative because most studies use MMP-9 as an output measurement and only determine whether MMP-9 levels change in response to a stimulus, not how the enzyme regulates ECM remodeling. The results of these studies will clarify the consequences of macrophage-derived MMP-9 on post- MI remodeling. Our multi-faceted approach will further advance the mechanistic understanding of the events that initiate post-MI LV remodeling, which may provide targets for translational research.
Heart failure is the inability of the heart to adequately supply the body with oxygen and is a leading cause of death in the United States. Of the 50,000 heart failure patients diagnosed each year, 70% have heart failure due to a previous heart attack (myocardial infarction;MI). The main objective of this grant is to use a mouse MI model to understand how the macrophage, an inflammatory cell that regulates wound healing, and matrix metalloproteinase-9, an enzyme in the macrophage that regulates scar formation, direct the response to MI.
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