Irisin protects against cardiac injury by inhibiting NLRP3 inflammasome-mediated pyroptosis during remodeling after infarction

Abstract

This study aimed to explore the cardioprotective mechanism of irisin in the context of cardiac injury. Utilizing a myocardial infarction (MI) mouse model, we investigated the therapeutic potential of recombinant human irisin (rhIrisin) administered for 28 days post-infarction. The efficacy of irisin treatment was evaluated through echocardiographic assessment of cardiac function and serum analysis of myocardial injury markers. Our research provided novel insights into the impacts of irisin on the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation and pyroptosis, assessed both in vivo in MI mice and in vitro in hypoxia/reoxygenation-treated H9C2 cells. Remarkably, irisin treatment significantly reduced levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and troponin I, indicating reduced myocardial injury. Echocardiography highlighted substantial improvements in left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and dimensions (LVIDd and LVIDs) in irisin-treated mice, underscoring enhanced cardiac function. Moreover, irisin was shown to significantly suppress the mRNA and protein expressions of key components involved in NLRP3 inflammasome pathway (NLRP3, ASC, caspase-1 (p20), and interleukin-18 (IL-18)) both in MI-induced mice and hypoxia/reoxygenation-treated cells. This study firstly reveals that the cardioprotective effect of irisin is mediated through the attenuation of NLRP3 inflammasome activation and pyroptosis, positioning irisin as a promising therapeutic agent for cardiac injury.