Cargando…
Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis
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 hyp...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010444/ https://www.ncbi.nlm.nih.gov/pubmed/29925877 http://dx.doi.org/10.1038/s41419-018-0726-3 |
_version_ | 1783333578057187328 |
---|---|
author | Zhao, Dajun Feng, Pan Sun, Yang Qin, Zhigang Zhang, Zhengbin Tan, Yanzhen Gao, Erhe Lau, Wayne Bond Ma, Xinliang Yang, Jian Yu, Shiqiang Xu, Xuezeng Yi, Dinghua Yi, Wei |
author_facet | Zhao, Dajun Feng, Pan Sun, Yang Qin, Zhigang Zhang, Zhengbin Tan, Yanzhen Gao, Erhe Lau, Wayne Bond Ma, Xinliang Yang, Jian Yu, Shiqiang Xu, Xuezeng Yi, Dinghua Yi, Wei |
author_sort | Zhao, Dajun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6010444 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60104442018-06-21 Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis Zhao, Dajun Feng, Pan Sun, Yang Qin, Zhigang Zhang, Zhengbin Tan, Yanzhen Gao, Erhe Lau, Wayne Bond Ma, Xinliang Yang, Jian Yu, Shiqiang Xu, Xuezeng Yi, Dinghua Yi, Wei Cell Death Dis Article 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. Nature Publishing Group UK 2018-06-20 /pmc/articles/PMC6010444/ /pubmed/29925877 http://dx.doi.org/10.1038/s41419-018-0726-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhao, Dajun Feng, Pan Sun, Yang Qin, Zhigang Zhang, Zhengbin Tan, Yanzhen Gao, Erhe Lau, Wayne Bond Ma, Xinliang Yang, Jian Yu, Shiqiang Xu, Xuezeng Yi, Dinghua Yi, Wei Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title | Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title_full | Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title_fullStr | Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title_full_unstemmed | Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title_short | Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
title_sort | cardiac-derived ctrp9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010444/ https://www.ncbi.nlm.nih.gov/pubmed/29925877 http://dx.doi.org/10.1038/s41419-018-0726-3 |
work_keys_str_mv | AT zhaodajun cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT fengpan cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT sunyang cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT qinzhigang cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT zhangzhengbin cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT tanyanzhen cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT gaoerhe cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT lauwaynebond cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT maxinliang cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT yangjian cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT yushiqiang cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT xuxuezeng cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT yidinghua cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis AT yiwei cardiacderivedctrp9protectsagainstmyocardialischemiareperfusioninjuryviacalreticulindependentinhibitionofapoptosis |