TRPC channels blockade abolishes septic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage

Abstract Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. The present study shows that the knockout of transient receptor potential canonical (TRPC) channel isoforms, TRPC1 and TRPC6, can strikingly ameliorate LPS-challenged heart failure and prolong survivability in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC’s molecular partner, calmodulin is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4’s Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Importantly, blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could markedly obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a powerful cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide new insights into the pathogenesis of septic cardiac dysfunction and suggest a novel approach for its treatment.