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

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 () and Wei Cao ()
Additional contact information
Na Tang: Northwest A&F University
Wen Tian: Fourth Military Medical University
Guang-Yuan Ma: Northwest A&F University
Xiong Xiao: Fourth Military Medical University
Lei Zhou: Northwest A&F University
Ze-Zhi Li: Northwest A&F University
Xiao-Xiao Liu: Fourth Military Medical University
Chong-Yao Li: the Affiliated Hospital of Northwest University
Ke-Han Wu: Northwest A&F University
Wenjuan Liu: Northwest A&F University
Xue-Ying Wang: Fourth Military Medical University
Yuan-Yuan Gao: Fourth Military Medical University
Xin Yang: Northwest A&F University
Jianzhao Qi: Northwest A&F University
Ding Li: Northwest A&F University
Yang Liu: Fourth Military Medical University
Wen-Sheng Chen: Fourth Military Medical University
Jinming Gao: Northwest A&F University
Xiao-Qiang Li: Fourth Military Medical University
Wei Cao: Northwest A&F University

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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/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.

Date: 2022
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DOI: 10.1038/s41467-022-35242-0

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