TRPV6 protects ER stress-induced apoptosis via ATF6α-TRPV6-JNK pathway in human embryonic stem cell-derived cardiomyocytes

Zhichao Li, Zhaoyue Meng, Jun Lu, Francis M. Chen, Wing Tak Wong, Gary Tse, Changbo Zheng, Wendy Keung, Kennis Tse, Ronald A. Li, Liwen Jiang, Xiaoqiang Yao

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Human pluripotent stem cell-derived cardiomyocytes have potential applications in disease modeling and drug screening. Therefore, it is important to understand the mechanisms and signaling pathways underlying the survival and death of these cells. Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding in the ER. Cells cope with ER stress by activating the unfolded protein response (UPR), a homeostatic signaling network that orchestrates the recovery of ER function. In the present study, we hypothesized that ER stress may upregulate the expression of transient receptor potential channel TRPV6, which in turn serves to protect human embryonic stem cell-derived cardiomyocytes (hESC-CMs) from ER stress-induced apoptotic cell death. Indeed, we found that ER stress induced by thapsigargin and tunicamycin led to increased expression of TRPV6 via ATF6α signaling branch. siRNA-mediated knockdown of TRPV6 aggravated ER stress-induced apoptotic cell death, whereas overexpression of TRPV6 attenuated ER stress-induced apoptosis in hESC-CMs. Furthermore, the signaling pathway downstream of TRPV6 was MAPK-JNK. Taken together, these results provide strong evidence that, under ER stress, TRPV6 is upregulated to protect hESC-CMs from apoptotic cell death via ATF6α-TRPV6-JNK pathway.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume120
DOIs
Publication statusPublished - Jul 2018
Externally publishedYes

Keywords

  • ATF6
  • ER stress
  • Human embryonic stem cells
  • JNK signaling pathway
  • TRPV6 channel

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