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Role of cardiac fibroblasts in myocardial dysfunction in mice with sepsis: effect of NLRP3 inflammasome activation (1096.7)

Background: Inflammasomes are intracellular platforms which promote maturation and releasing of IL‐1β and IL‐18. Cardiac fibroblast is the most abundant non‐cardiomyocytes within the heart. The aim of the present study was to evaluate whether sepsis activates NLRP3 inflammasome in cardiac fibroblasts and subsequently affects function of cardiomyocytes through IL‐1β thereby results in myocardial dysfunction. Materials and Methods: NLPR3, procaspase‐1, caspase‐1 p10, pro‐IL‐1β and IL‐1β in cardiac fibroblasts were assessed with Western blot or ELISA. Cardiomyocyte intracellular cAMP was assessed with direct immunoassay kit. Mouse model of sepsis was induced by intraperitoneal injection of LPS. Mouse myocardial function was evaluated with a mouse pressure‐volume loop analysis system. Results: Treatment of cardiac fibroblasts with LPS resulted in activation of capase‐1 (increased p10) and induced maturation and releasing of IL‐1β. Genetically (siRNA) and pharmacologically (Glyburide) inhibition of NLRP3 inflammasome in cardiac fibroblasts blocked the LPS‐induced activation of the caspase‐1, as well as the maturation and releasing of the IL‐1β. Inhibition of NLRP3 inflammasome in cardiac fibroblasts prevented the decrease in intracellular cAMP in cardiomyocyte conditioned with supernatants of cardiac fibroblasts with LPS. Inhibition of the NLRP3 inflammasome attenuated the myocardial dysfunction in mice with sepsis. Conclusions: Activation of NLRP3 inflammasome in cardiac fibroblasts results in increased IL‐1β production which mediates the cardiac fibroblast‐cardiomyocyte interaction and promotes the induction of myocardial dysfunction in mice with sepsis. (HSFO GIA 2012‐000212 to TR).