Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis
| Autor: | Erhe Gao, Dinghua Yi, Wei Yi, Yanzhen Tan, Pan Feng, Zhigang Qin, Wayne Bond Lau, Yang Sun, Jian Yang, Xuezeng Xu, Zhengbin Zhang, Xin-Liang Ma, Dajun Zhao, Shiqiang Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research Cardiotonic Agents Heart Ventricles Immunology Cell Apoptosis Myocardial Reperfusion Injury Models Biological Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience medicine Animals Myocytes Cardiac lcsh:QH573-671 Cyclic AMP Response Element-Binding Protein Autocrine signalling Protein kinase A Glycoproteins Mice Knockout biology Chemistry lcsh:Cytology Myocardium Endoplasmic reticulum Cell Biology medicine.disease Cyclic AMP-Dependent Protein Kinases Cell biology Mice Inbred C57BL Autocrine Communication Phenotype 030104 developmental biology medicine.anatomical_structure biology.protein Adiponectin Signal transduction Calreticulin Reperfusion injury |
| Zdroj: | Cell Death and Disease, Vol 9, Iss 7, Pp 1-13 (2018) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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