Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis

Dajun Zhao,Pan Feng,Shiqiang Yu,Xuezeng Xu,Zhigang Qin,Zhengbin Zhang,Erhe Gao,Jian Yang,Xinliang Ma,Yang Sun,Wayne Bond Lau,Wei Yi,Yanzhen Tan,Dinghua Yi

doi:10.1038/s41419-018-0726-3

Abstract

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.

Highlights

They maintain cardiac homeostasis and modulate patho-Ischemic heart disease (IHD) is the leading cause of death and disability worldwide[1,2]
Cardiac C1q/TNF-related protein 9 (CTRP9) overexpression mice manifested smaller myocardial infarct size (P < 0.05, Fig. 1j). These data suggest that cardiac-derived CTRP9 directly protects against myocardial ischemia/reperfusion (MI/R) injury
In the present study, we provide the first evidence that cardiac-derived CTRP9 exerts cardioprotection against MI/R injury in an autocrine manner

Summary

Introduction

They maintain cardiac homeostasis and modulate patho-Ischemic heart disease (IHD) is the leading cause of death and disability worldwide[1,2]. Some cardiokines are secreted during ischemic stress, and function to salvage viable myocardial structure and function via anti-apoptotic and antiinflammatory properties[6,7,8,9]. C1q/TNF-related protein 9 (CTRP9) is a member of the adiponectin (APN) paralog CTRP family, initially identified as an adipokine modulating metabolic and. These authors contributed : Dajun Zhao, Pan Feng, Yang Sun, Zhigang Qin. Official journal of the Cell Death Differentiation Association. Whether cardiac-derived CTRP9 protects against MI/R injury (and if so, by what mechanisms) is unknown

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