The Role of Gasdermin-D/Interleukin-1 Nexus in Atrial Arrhythmogenesis

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PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Enhanced activation of ‘NACHT, LRR and PYD domains- containing protein 3’ (NLRP3) inflammasome plays a causal role in promoting proarrhythmic events associated with AF development. Activation of NLRP3 inflammasome produces two major effectors: interleukin (IL)-1b and cleaved (active) N-terminal gasdermin-D (GSDMDNT). Results from parent grant suggest that that GSDMD could promote atrial arrhythmogenesis by previously unrecognized pyroptosis-independent alternative functions in cardiomyocytes and the membrane-repair machinery via ESCRT III may prevent excessive cell death upon inflammasome activation during AF development. In this application, we will elucidate the alternative function of GSDMDNT and the involvement of ESCRT III-mediated membrane repair machinery in cardiomyocytes.