Abstract
Cardiac dysfunction is a vital complication of endotoxemia (ETM) with limited therapeutic options. Transient receptor potential canonical channel (TRPC)1 was involved in various heart diseases. While, the role of TRPC1 in ETM-induced cardiac dysfunction remains to be defined. In this study, we found that TRPC1 protein expression was significantly upregulated in hearts of lipopolysaccharide (LPS)-challenged mice. What's more, TRPC1 knockdown significantly alleviated LPS-induced cardiac dysfunction and injury. Further myocardial mRNA-sequencing analysis revealed that TRPC1 might participate in pathogenesis of ETM-induced cardiac dysfunction via mediating myocardial apoptosis and autophagy. Data showed that knockdown of TRPC1 significantly ameliorated LPS-induced myocardial apoptotic injury, cardiomyocytes autophagosome accumulation, and myocardial autophagic flux. Simultaneously, deletion of TRPC1 reversed LPS-induced molecular changes of apoptosis/autophagy signaling pathway in cardiomyocytes. Moreover, TRPC1 could promote LPS-triggered intracellular Ca2+ release, subsequent calpain activation and caveolin-1 degradation. Either blocking calpain by PD150606 or enhancing the amount of caveolin-1 scaffolding domain that interacts with TRPC1 by cell-permeable peptide cavtratin significantly alleviated the LPS-induced cardiac dysfunction and cardiomyocytes apoptosis/autophagy. Furthermore, cavtratin could inhibit LPS-induced calpain activation in cardiomyocytes. caveolin-1 could directly interact with calpain 2 both in vivo and in vitro. Importantly, cecal ligation and puncture-stimulated cardiac dysfunction and mortality were significantly alleviated in Trpc1-/- and cavtratin-treated mice, which further validated the contribution of TRPC1-caveolin-1 signaling axis in sepsis-induced pathological process. Overall, this study indicated that TRPC1 could promote LPS-triggered intracellular Ca2+ release, mediate caveolin-1 reduction, and in turn activates calpain to regulate myocardial apoptosis and autophagy, contributing to ETM-induced cardiac dysfunction of mice.