Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis.
Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis.
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心脏来源的 CTRP9 通过钙网蛋白依赖性细胞凋亡抑制来防止心肌缺血/再灌注损伤
DOI：
10.1038/s41419-018-0726-3
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发表时间：
2018-06-20
影响因子：
9
通讯作者：
Yi W
中科院分区：
文献类型：
--
作者：
Zhao D;Feng P;Sun Y;Qin Z;Zhang Z;Tan Y;Gao E;Lau WB;Ma X;Yang J;Yu S;Xu X;Yi D;Yi W
心肌细胞因子在维持正常心脏功能和对急性心肌损伤的反应中起着重要作用。研究表明，心脏本身是C1 q/TNF相关蛋白9（CTRP 9）的重要来源。然而，心脏来源的CTRP 9的生物学作用仍不清楚。我们假设心脏来源的CTRP 9作为一种心因子对急性心肌缺血/再灌注（MI/R）损伤作出反应。我们通过基因操作和CTRP 9敲除（CTRP 9-KO）动物模型探索了心脏来源的CTRP 9在MI/R损伤中的作用。心脏CTRP 9的抑制加剧，而其过表达改善，左心室功能障碍和心肌细胞凋亡。在体外模拟缺血/再灌注（SI/R）后，内皮细胞CTRP 9表达不变，而心肌细胞CTRP 9水平下降。心肌细胞CTRP 9过表达抑制SI/R诱导的细胞凋亡，CTRP 9抗体消除了这种作用。从机制上讲，心肌来源的CTRP 9激活了抗凋亡信号通路，并抑制了MI/R损伤中内质网（ER）应激相关的凋亡。值得注意的是，CTRP 9与位于心肌细胞表面和细胞质中的ER分子伴侣钙网蛋白（CRT）相互作用。CTRP 9-CRT相互作用激活蛋白激酶A-cAMP反应元件结合蛋白（PKA-CREB）信号通路，通过自分泌CTRP 9的功能性中和而阻断。CRT或PKA的抑制减弱了心脏衍生的CTRP 9对MI/R损伤的抗凋亡作用。我们在CTRP 9-KO大鼠中进一步证实了这些发现。总之，这些结果表明，心肌细胞来源的自分泌CTRP 9通过CRT联合、PKA-CREB途径的激活、最终抑制心肌细胞凋亡来保护免受MI/R损伤。
Cardiokines play an essential role in maintaining normal cardiac functions and responding to acute myocardial injury. Studies have demonstrated the heart itself is a significant source of C1q/TNF-related protein 9 (CTRP9). However, the biological role of cardiac-derived CTRP9 remains unclear. We hypothesize cardiac-derived CTRP9 responds to acute myocardial ischemia/reperfusion (MI/R) injury as a cardiokine. We explored the role of cardiac-derived CTRP9 in MI/R injury via genetic manipulation and a CTRP9-knockout (CTRP9-KO) animal model. Inhibition of cardiac CTRP9 exacerbated, whereas its overexpression ameliorated, left ventricular dysfunction and myocardial apoptosis. Endothelial CTRP9 expression was unchanged while cardiomyocyte CTRP9 levels decreased after simulated ischemia/`reperfusion (SI/R) in vitro. Cardiomyocyte CTRP9 overexpression inhibited SI/R-induced apoptosis, an effect abrogated by CTRP9 antibody. Mechanistically, cardiac-derived CTRP9 activated anti-apoptotic signaling pathways and inhibited endoplasmic reticulum (ER) stress-related apoptosis in MI/R injury. Notably, CTRP9 interacted with the ER molecular chaperone calreticulin (CRT) located on the cell surface and in the cytoplasm of cardiomyocytes. The CTRP9–CRT interaction activated the protein kinase A-cAMP response element binding protein (PKA-CREB) signaling pathway, blocked by functional neutralization of the autocrine CTRP9. Inhibition of either CRT or PKA blunted cardiac-derived CTRP9’s anti-apoptotic actions against MI/R injury. We further confirmed these findings in CTRP9-KO rats. Together, these results demonstrate that autocrine CTRP9 of cardiomyocyte origin protects against MI/R injury via CRT association, activation of the PKA-CREB pathway, ultimately inhibiting cardiomyocyte apoptosis.
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影响因子：
13.6
作者：
Doroudgar S;Glembotski CC
通讯作者：
Glembotski CC
影响因子：
5
作者：
Chai, WX;Mehrotra, S;Schoemaker, RG
通讯作者：
Schoemaker, RG
影响因子：
64.8
作者：
BURNS, K;DUGGAN, B;MICHALAK, M
通讯作者：
MICHALAK, M
DOI：
10.1084/jem.194.6.781
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ogden CA;deCathelineau A;Hoffmann PR;Bratton D;Ghebrehiwet B;Fadok VA;Henson PM
通讯作者：
Henson PM
影响因子：
64.5
作者：
CAMACHO, P;LECHLEITER, JD
通讯作者：
LECHLEITER, JD