Inflammasome activation promotes myocardial injury and associated atherosclerosis following myocardial IRI

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We recently demonstrated that the cytoprotective coagulation protease activated protein C (aPC) protects from myocardial ischemia-reperfusion injury (IRI) by restricting Nlrp3 inflammasome activation, revealing a novel anti-inflammatory target of aPC. The protective effect of aPC in the heart was mimicked by 3K3A-aPC (a cyto-protective, non-anti-coagulant aPC mutant) or parmodulin-2 (a biased agonist mimicking aPC signaling via proteinase-activated receptor 1), but was lost in mice expressing a hyperactive NLRP3 variant. In addition, inflammasome activation and associated cell death (pyroptosis) preceded apoptosis in myocardial IRI. Inflammasome activation was apparent in both immune and non-immune cells (cardiomyocyte and cardiac fibroblast) in myocardial IRI. While providing novel insights, important questions remain open: 1) It is unknown whether the induction of apoptosis at later stages following IRI may prevent excessive inflammation, thus providing protection in IRI. 2) The mechanisms controlling inflammasome activation in myocardial IRI are not known. 3) The relative contribution of cardiac resident cells and immune cells to inflammasome activation in myocardial IRI remains unclear. 4) The potential role of the non-canonical inflammasome are unknown. 5) It is not known whether the inflammasome activation associated with myocardial IRI contributes to the accelerated atherosclerosis following myocardial IRI.Based on published and preliminary work we will study the following goals to address these questions: Goal 1: Defining the causal contribution of pyroptosis versus apoptosis in myocardial IRI and the cell-autonomous effects of inflammasome activation in cardiac resident cells.Goal 2: Deciphering the mechanism through which aPC regulates inflammasome activity in myocardial IRI and cardiac dysfunction.Goal 3: Characterizing the relevance of inflammasome activation for myocardial IRI-mediated accelerated atherosclerosis.Collectively, we expect that these studies will provide novel insights into the mechanism through which inflammasome activation in myocardial IRI contributes to myocardial damage and dysfunction and to an acceleration of atherosclerosis. The delineation of these mechanisms may identify new therapeutic targets (e.g. targeting a specific cell-type or only the canonical inflammasome activation pathway) to combat the consequences of myocardial IRI.