Format

Send to

Choose Destination
EMBO Mol Med. 2018 Mar;10(3). pii: e8237. doi: 10.15252/emmm.201708237.

CRTH2 promotes endoplasmic reticulum stress-induced cardiomyocyte apoptosis through m-calpain.

Author information

1
Department of Pharmacology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
2
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
3
Department of Biology, University of Miami College of Arts and Science, Miami, FL, USA.
4
Medical Research Department of Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou Guangdong, China.
5
McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
6
Department of Pharmacology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China yujun_shen@yahoo.com yuying@tmu.edu.cn.

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.

KEYWORDS:

CRTH2; calpain; cardiomyocyte apoptosis; endoplasmic reticulum stress; prostaglandin D2

PMID:
29335338
PMCID:
PMC5840549
DOI:
10.15252/emmm.201708237
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center