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

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 no...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840549/
https://www.ncbi.nlm.nih.gov/pubmed/29335338
http://dx.doi.org/10.15252/emmm.201708237
Descripción
Sumario: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 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 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.