CRTH2 promotes endoplasmic reticulum stress-induced cardiomyocyte apoptosis through m-calpain.
CRTH2 promotes endoplasmic reticulum stress-induced cardiomyocyte apoptosis through m-calpain.
复制标题
CRTH2通过m-钙蛋白酶促进内质网应激诱导的心肌细胞凋亡
DOI：
10.15252/emmm.201708237
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发表时间：
2018-03
影响因子：
11.1
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Zuo S;Kong D;Wang C;Liu J;Wang Y;Wan Q;Yan S;Zhang J;Tang J;Zhang Q;Lyu L;Li X;Shan Z;Qian L;Shen Y;Yu Y
心肌细胞凋亡与缺血性心脏病和化疗引起的心肌病有关。 2 型辅助 T 细胞 (CRTH2) 上表达的趋化受体同源分子在心脏中高度表达。然而，其在缺血性心肌病中的具体作用尚不完全清楚。在这里，我们证明 CRTH2 破坏通过抑制心肌细胞凋亡，显着改善心肌梗死和阿霉素攻击后小鼠的心脏恢复。从机制上讲，CRTH2 激活通过 caspase-12 依赖性途径特异性促进内质网 (ER) 应激诱导的心肌细胞凋亡。阻断 m-calpain 通过抑制 caspase-12 活性来阻止 ER 应激下 CRTH2 介导的心肌细胞凋亡。 CRTH2 与 Gαq 偶联可引发细胞内 Ca2+ 通量并激活心肌细胞中的 m-calpain/caspase-12 级联。 caspase-4（人类 caspase-12 的替代品）的敲低可显着减轻 CRHT2 激活诱导的人心肌细胞缺氧反应中的细胞凋亡。我们的研究结果揭示了 CRTH2 在促进 ER 应激诱导的心肌细胞凋亡中的意外作用，表明 CRTH2 抑制具有治疗缺血性心肌病的潜力。
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.