MMP-9 Roles in the Aging Myocardial Response to Ischemia

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DESCRIPTION (provided by applicant): Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. Identifying the events that induce adverse cardiac remodeling post-MI will provide therapeutic targets to prevent, slow, or reverse progression to heart failure. A major risk factor for a poor response to MI is age. With age, there is an increased infiltration of macrophages into the left ventricle (LV), which stimulates extracellular matrix (ECM) accumulation and leads to a subtle but significant change in LV function evidenced by reduced early (E) to late (A) filling ratios. Post-MI, macrophage infiltration and ECM accumulation are driving events, and matrix metalloproteinase (MMP)-9 regulates both of these processes. MMP-9 deletion attenuates the cardiac response to aging, in part by shifting macrophage polarization from a pro-inflammatory M1 state to an anti- inflammatory M2 state. Our preliminary data demonstrate that MMP-9 levels are much increased in older mice at day 7 post-MI, and this in-crease in MMP-9 yields more M1 macrophages to extend the inflammatory response and delay the healing phase. MMP-9 deletion restores the M1 and M2 polarization balance. This renewal proposal will address the central hypothesis that during the MI response in aging mice, MMP-9 enhances pro-inflammatory M1 polarization and attenuates anti- inflammatory M2 polarization to induce adverse remodeling. To test our hypothesis, we will determine macrophage polarization kinetics in young (3-6 month old) and old (18-23 month old) wild type and MMP-9 null mice. We will evaluate how MMP-9 activates macrophage polarization and how this process is altered with aging (aim 1), whether young hearts can be switched to an old phenotype by stimulating M1 macrophage polarization (aim 2), and whether old hearts can be switched to a young phenotype by stimulating M2 macrophage polarization (aim 3). This proposal is unique, because most studies use MMP-9 as an output measurement whereby we will use MMP-9 as a major input. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomics, 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 have high significance for the aging veteran population.