Project Summary Hydrogen sulfide (H2S) is a powerful gasotransmitter, which has been shown to possess robust protective effects against ischemia-related injuries in the heart and other organs. Recent innovative studies by the PI and colleagues have identified regulation of endogenous levels of H2S to mediate the cardioprotective effect of phosphodiesterase-5 inhibitor, tadalafil, as well as a potent nitric oxide (NO)-independent guanylate cyclase activator, Cinaciguat, in the mouse heart. More recent studies from the PI's laboratory demonstrated the infarct-sparing and anti-inflammatory benefits of exogenous H2S against ischemia/reperfusion (I/R) injury as well as the role of cystathionine-γ-lyase-driven H2S generation in mediating the cardioprotective effects of gene therapy with protein kinase G. The purpose of this application is to further investigate the novel mechanisms by which H2S attenuates ischemic cardiomyopathy and inflammasome-mediated adverse remodeling in the failing heart. We will test the following hypotheses: 1) To investigate the protective effects of H2S on prevention of adverse remodeling post myocardial infarction (MI) and mitigation of ischemic heart failure. We will study the impact of H2S on LV scar size, function and remodeling. 2) To determine the chronic anti- inflammatory effect of H2S through suppression of NLRP3-inflammasome and the evolution of ischemic cardiomyopathy. 3) To study the role of H2S in attenuation of mitochondrial damage and propagation of inflammatory injury following MI by preserving MAVS and suppressing cofilin-2. These studies will be the first to demonstrate the protective effects of H2S for prevention of adverse remodeling following MI and also its potential therapeutic utility in the failing heart, possibly through attenuation of inflammasome-mediated maladaptive signaling. This is especially novel and the results will have a tremendous impact on further endorsing H2S as a potent therapeutic agent for ischemic heart failure. Moreover, these studies will provide novel mechanistic information by which new synthetic pharmacological agents with precisely controlled H2S release lead to improvement in overall cardiovascular health.