Open AccessCRTH2 promotes endoplasmic reticulum stress‐induced cardiomyocyte apoptosis through m‐calpain
Author(s) -
Zuo Shengkai,
Kong Deping,
Wang Chenyao,
Liu Jiao,
Wang Yuanyang,
Wan Qiangyou,
Yan Shuai,
Zhang Jian,
Tang Juan,
Zhang Qianqian,
Lyu Luheng,
Li Xin,
Shan Zhixin,
Qian Li,
Shen Yujun,
Yu Ying
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708237
Subject(s) - endoplasmic reticulum , apoptosis , microbiology and biotechnology , calpain , unfolded protein response , myocyte , caspase , caspase 3 , caspase 12 , cardiomyopathy , biology , cancer research , programmed cell death , chemistry , medicine , heart failure , biochemistry , enzyme
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 ( CRTH 2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH 2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH 2 activation specifically facilitated endoplasmic reticulum ( ER ) stress‐induced cardiomyocyte apoptosis via caspase‐12‐dependent pathway. Blockage of m‐calpain prevented CRTH 2‐mediated cardiomyocyte apoptosis under ER stress by suppressing caspase‐12 activity. CRTH 2 was coupled with G αq to elicit intracellular Ca 2+ flux and activated m‐calpain/caspase‐12 cascade in cardiomyocytes. Knockdown of caspase‐4, an alternative to caspase‐12 in humans, markedly alleviated CRHT 2 activation‐induced apoptosis in human cardiomyocyte response to anoxia. Our findings revealed an unexpected role of CRTH 2 in promoting ER stress‐induced cardiomyocyte apoptosis, suggesting that CRTH 2 inhibition has therapeutic potential for ischemic cardiomyopathy.