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

Abstract

4 Intracellular Ca dysregulation is a key marker in septic cardiac dysfunction; however, regulation of 5 the classic Ca regulatory modules cannot successfully abolish this symptom. The present study shows that 6 the knockout of transient receptor potential canonical (TRPC) channel isoforms, TRPC1 and TRPC6, can 7 strikingly ameliorate LPS-challenged heart failure and prolong survivability in mice. The LPS-triggered Ca 8 release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by 9 Trpc1 or Trpc6 knockout. Meanwhile, TRPC’s molecular partner, calmodulin is uncoupled during Trpc1 or 10 Trpc6 deficiency and binds to TLR4’s Pococurante site and atypical isoleucine-glutamine-like motif to block 11 the inflammation cascade. Importantly, blocking the C-terminal CaM/IP3R binding domain in TRPC with 12 chemical inhibitor could markedly obstruct the Ca leak and TLR4-mediated inflammation burst, 13 demonstrating a powerful cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings 14 provide new insights into the pathogenesis of septic cardiac dysfunction and suggest a novel approach for its 15 treatment. 16