2. Academic Validation
  3. TRPC1 contributes to endotoxemia-induced myocardial dysfunction via mediating myocardial apoptosis and autophagy

TRPC1 contributes to endotoxemia-induced myocardial dysfunction via mediating myocardial apoptosis and autophagy

  • Pharmacol Res. 2022 Jul;181:106262. doi: 10.1016/j.phrs.2022.106262.
Wen Tian 1,  Shao-Yuan Liu 2,  Meng Zhang 3,  Jing-Ru Meng 4,  Na Tang 5,  Ying-Da Feng 6,  Yang Sun 7,  Yuan-Yuan Gao 8,  Lei Zhou 9,  Wei Cao 10,  Xiao-Qiang Li 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: tianwen012@qq.com.
  • 2 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: 1367866133@qq.com.
  • 3 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: 531619916@qq.com.
  • 4 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: mjrfmmu@fmmu.edu.cn.
  • 5 Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: donnao7@163.com.
  • 6 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: fyd1991@sina.com.
  • 7 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: ysun1145@163.com.
  • 8 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: 472963932@qq.com.
  • 9 Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: 835699176@qq.com.
  • 10 Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: caowei@nwafu.edu.cn.
  • 11 Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China; Shaanxi Key Laboratory of "Qin Medicine" Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, Shaanxi 710032, China. Electronic address: xxqqli@fmmu.edu.cn.
PMID: 35598715 DOI: 10.1016/j.phrs.2022.106262
Abstract

Cardiac dysfunction is a vital complication of endotoxemia (ETM) with limited therapeutic options. Transient receptor potential canonical channel (TRPC)1 was involved in various heart diseases. While, the role of TRPC1 in ETM-induced cardiac dysfunction remains to be defined. In this study, we found that TRPC1 protein expression was significantly upregulated in hearts of lipopolysaccharide (LPS)-challenged mice. What's more, TRPC1 knockdown significantly alleviated LPS-induced cardiac dysfunction and injury. Further myocardial mRNA-sequencing analysis revealed that TRPC1 might participate in pathogenesis of ETM-induced cardiac dysfunction via mediating myocardial Apoptosis and Autophagy. Data showed that knockdown of TRPC1 significantly ameliorated LPS-induced myocardial apoptotic injury, cardiomyocytes autophagosome accumulation, and myocardial autophagic flux. Simultaneously, deletion of TRPC1 reversed LPS-induced molecular changes of Apoptosis/Autophagy signaling pathway in cardiomyocytes. Moreover, TRPC1 could promote LPS-triggered intracellular CA2+ release, subsequent calpain activation and caveolin-1 degradation. Either blocking calpain by PD150606 or enhancing the amount of caveolin-1 scaffolding domain that interacts with TRPC1 by cell-permeable peptide cavtratin significantly alleviated the LPS-induced cardiac dysfunction and cardiomyocytes Apoptosis/Autophagy. Furthermore, cavtratin could inhibit LPS-induced calpain activation in cardiomyocytes. caveolin-1 could directly interact with calpain 2 both in vivo and in vitro. Importantly, cecal ligation and puncture-stimulated cardiac dysfunction and mortality were significantly alleviated in Trpc1-/- and cavtratin-treated mice, which further validated the contribution of TRPC1-caveolin-1 signaling axis in sepsis-induced pathological process. Overall, this study indicated that TRPC1 could promote LPS-triggered intracellular CA2+ release, mediate caveolin-1 reduction, and in turn activates calpain to regulate myocardial Apoptosis and Autophagy, contributing to ETM-induced cardiac dysfunction of mice.

Keywords

Apoptosis; Autophagy; Calpain; Caveolin-1; TRPC1.

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