MMP-12 as an Endogenous Post-MI Resolution Promoting Factor

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Abstract About one in four myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 5-year mortality rate of 50%. The goal of this project is to understand post-MI roles of matrix metalloproteinase-12 (MMP-12) by establishing how MMP-12 serves as a resolution promoting factor to stimulate the transition from inflammation to repair. We hypothesize that MMP-12 regulates individual neutrophil, macrophage, and fibroblast physiology to promote the resolution of post-MI inflammation and stimulate repair. Our specific aims will explore the mechanism whereby MMP-12 turns off pro- inflammation (aim 1), initiates anti-inflammation (aim 2), and promotes repair (aim 3). Innovation lies in the evaluation of MMP-12 post-MI to connect early cell functions to late remodeling outcomes and in the integration of multi-discipline approaches to explore the mechanisms whereby MMP-12 regulates resolution. This study will drive forward the understanding of the molecular basis of LV remodeling and will identify novel intervention targets directed at MMP-12.