Abstract 10959: Inhibition of CTRP9, a Novel and Cardiac-Abundantly Expressed Cell Survival Molecule, by TNFα-Initiated Oxidative Signaling Contributes to Exacerbated Cardiac Injury in Diabetic Mice
Of primarily adipocyte origin, the adipokine adiponectin (APN) is also expressed in cardiomyocytes. However, as cardiac expression of APN is extremely low (<1/120,000 of adipocytes), its physiological significance is unclear. The recently identified C1q/TNF-related proteins (CTRPs) share similar metabolic regulatory functions with APN. The current study determined extent of cardiac expression of various CTRPs, their potential cardioprotective function, and investigated whether and how the diabetic condition might regulate cardiac CTRP expression. Several CTRPs (1,4,7, and 9) are expressed in the heart at levels significantly greater than APN. Cardiac expression of CTRP9, which shares greatest homology with APN and is the only CTRP capable of heterodimerization with APN, notably exceeds APN >100 fold. Furthermore, local cardiac CTRP9 levels are 1.6-fold greater than plasma CTRP9 concentrations (P<0.05). In high-fat diet-induced diabetic mice, cardiac CTRP9 expression was significantly reduced (P<0.01). When cardiac CTRP9 expression was knocked down to the same extent observed in diabetic mice, myocardial ischemia/reperfusion injury increased significantly. Among various pro-inflammatory molecules augmented in diabetes, TNFα exerted the strongest inhibition upon cardiac expression of CTRP9 mRNA (-75%) and protein (-60%), and significantly reduced PPARγ, a known transcription factor promoting APN expression. Tiron (a cell permeable antioxidant) or rosiglitazone (a PPARγ agonist) reversed the inhibitory effect of TNFα upon PPARγ and CTRP9. Finally, in vivo CTRP9 administration to diabetic mice significantly attenuated generation of NADPH oxidase and superoxide, reduced infarct size, apoptotic index, and augmented cardiac function post-MI/R. We demonstrate for the first time that CTRP9 is a cardiac abundantly-expressed cell-survival molecule, and its downregulation by TNFα-initiated oxidative signaling/PPARγ-suppression contributes to exacerbated diabetic cardiac injury. Preservation of CTRP9 expression or augmentation of CTRP9-initiated signaling may represent potential avenues mitigating ischemic diabetic cardiac injury.
- © 2012 by American Heart Association, Inc.