TRPC channels blockade abolishes endotoxemic 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. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival 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. Blocking the C-terminal CaM/I

SUBMITTER: Tang N 

PROVIDER: S-EPMC9718841 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature