CORM‐3 derived CO suppresses NLRP3 inflammasome in cardiac fibroblasts and protects cardiomyocytes from apoptosis in mice with sepsis (1096.6)

Abstract

The study is to examine the role of CO derived from CORM‐3 on NLRP3 inflammasome activation in cardiac fibroblast (CF) and its effect on cardiomyocyte apoptosis and myocardial dysfunction in mice with sepsis. Methods: CFs were primed with LPS and followed by ATP treatment with or without CORM‐3. CF NLRP3 expression and NLRP3 inflammasome activation assessed. Cardiomyocyte apoptosis and myocardial function were measured in mice with LPS. Results: LPS priming and ATP treatment to CFs resulted in NLRP3 inflammasome activation as indicated by increase in cleaved caspase‐1 p20 and matured IL‐1β. CFs with NLRP3 siRNA abolished caspase‐1 cleavage and IL‐1β maturation. CORM‐3 attenuated the increase in NLRP3 and pro‐IL‐1β expression in LPS primed CFs and prevented NLRP3 inflammasome activation. CORM‐3 inhibited NLRP3‐mediated ASC pyroptosome formation. Myocardial NLRP3, pro‐capase‐1, p20, pro‐IL‐1β and IL‐1β were increased, cardiomyocyte apoptosis was induced and myocardial contractility was decreased in mice with LPS. CORM3 prevented the myocardial NLPR3 inflammasome activation, attenuated cardiomyocytes apoptosis, and improved cardiac function in mice with LPS. Conclusions: CORM‐3‐derived CO suppresses NLRP3 inflammasome priming and activation in CFs and protects myocardium from apoptosis and dysfunction in mice with endotoxemia. (HSFO 2012‐000212)Grant Funding Source: Heart and Stroke Foundation of Ontario