Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses

Sudhir Pandey, Chia Hua Kuo, William Shao Tsu Chen, Yu Lan Yeh, Wei Wen Kuo, Ray Jade Chen, Cecilia Hsuan Day, Pei Ying Pai, Tsung Jung Ho, Chih Yang Huang

研究成果: 雜誌貢獻文章同行評審

摘要

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

原文英語
頁(從 - 到)143-152
頁數10
期刊Molecular and Cellular Biochemistry
477
發行號1
DOIs
出版狀態已發佈 - 1月 2022

ASJC Scopus subject areas

  • 分子生物學
  • 臨床生物化學
  • 細胞生物學

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