Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. The identification of events that stimulate adverse remodeling of the left ventricle (LV) post-MI, therefore, will provide therapeutic targets to prevent, slow, or reverse the progression to heart failure. A major risk factor for a poor response to MI is age. We have observed that cardiac aging, in the absence of pathology, induces macrophage infiltration into the left ventricle (LV), increases matrix metalloproteinase-9 (MMP-9) levels in the plasma and the LV, decreases fibroblast function, alters LV structure, and diminishes LV function. Post-MI, extracellular matrix (ECM) remodeling is a driving event, and intial analysis of matrix metalloproteinase-9 (MMP-9) functions in remodeling suggest that this particular MMP predominantly influences extracellular signaling, ECM protein turnover, and fibroblast functions. MMP-9, therefore, is potentially relevant in both the pre- and post-MI settings. The goal of this project, accordingly, is to understand the role of aging on ECM, fibroblast, and macrophage responses to MI. This proposal will focus on elucidating unique MMP-9 driven mechanisms to critically test the hypothesis is that aging induces a baseline increase in MMP-9 and ECM levels, which alters ECM, fibroblast, and macrophage responses to MI. Using wild type and MMP-9 null mice, we will determine which MMP-9 mediated events most influence LV remodeling. To test our hypothesis, we will determine how ECM patterns (aim 1), fibroblast function (aim 2), and macrophage phenotypes (aim 3) regulate the MI response. This proposal is unique because most studies use MMP-9 as an output measurement and only determine whether levels change in response to a stimulus, not how the enzyme regulates ECM remodeling. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomic, and histological approaches to further advance the mechanistic understanding of the origins of post-MI LV remodeling and provide targets for translational research. The results of these studies will clarify the consequences of aging on post-MI remodeling.
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 aging influences scar formation by regulating the extracellular matrix environment and two cell types, the fibroblast and macrophage.
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