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

• DOI: 10.1038/s41467-022-35242-0
• Publication Date: 2022-12-02T18:04:20Z
• Authors: Na Tang; Wen Tian; Guang-Yuan Ma; Xiong Xiao; Lei Zhou; Ze-Zhi Li; Xiao-Xiao Liu; Chong-Yao Li; Ke-Han Wu; Wenjuan Liu; Xue-Ying Wang; Yuan-Yuan Gao; Xin Yang; Jianzhao Qi; Ding Li; Yang Liu; Wen-Sheng Chen; Jinming Gao; Xiao-Qiang Li; Wei Cao
• Keywords: Lipopolysaccharides; Inflammation; Heart Failure; 0301 basic medicine; 0303 health sciences; Science; Q; Article; Endotoxemia; 3. Good health; Toll-Like Receptor 4; Mice; 03 medical and health sciences; Transient Receptor Potential Channels; TRPC6 Cation Channel; Animals; Craniocerebral Trauma

AbstractIntracellular 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/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment.