CRTH2 promotes endoplasmic reticulum stress‐induced cardiomyocyte apoptosis through m‐calpain

Autor: Shengkai Zuo, Deping Kong, Chenyao Wang, Jiao Liu, Yuanyang Wang, Qiangyou Wan, Shuai Yan, Jian Zhang, Juan Tang, Qianqian Zhang, Luheng Lyu, Xin Li, Zhixin Shan, Li Qian, Yujun Shen, Ying Yu
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 10, Iss 3, Pp 1-17 (2018)
Druh dokumentu: article
ISSN: 20170823
1757-4676
1757-4684
DOI: 10.15252/emmm.201708237
Popis: Abstract Apoptotic death of cardiac myocytes is associated with ischemic heart disease and chemotherapy‐induced cardiomyopathy. Chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH2 activation specifically facilitated endoplasmic reticulum (ER) stress‐induced cardiomyocyte apoptosis via caspase‐12‐dependent pathway. Blockage of m‐calpain prevented CRTH2‐mediated cardiomyocyte apoptosis under ER stress by suppressing caspase‐12 activity. CRTH2 was coupled with Gαq to elicit intracellular Ca2+ flux and activated m‐calpain/caspase‐12 cascade in cardiomyocytes. Knockdown of caspase‐4, an alternative to caspase‐12 in humans, markedly alleviated CRHT2 activation‐induced apoptosis in human cardiomyocyte response to anoxia. Our findings revealed an unexpected role of CRTH2 in promoting ER stress‐induced cardiomyocyte apoptosis, suggesting that CRTH2 inhibition has therapeutic potential for ischemic cardiomyopathy.
Databáze: Directory of Open Access Journals
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