C1q/TNF-Related Protein-3, a Newly Identified Adipokine, Is a Novel Anti-Apoptotic, Pro-Angiogenic, and Cardioprotective Molecule in the Ischemic Mouse Heart
Background—Obesity/diabetes adversely affects post-ischemic heart remodeling via incompletely understood mechanisms. C1q/TNF-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The current study determined whether CTRP3 may regulate post-ischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms.
Methods and Results—Male adult mice were subjected to myocardial infarction (MI) via left anterior descending coronary artery occlusion. Both the effect of MI upon endogenous CTRP3 expression/production and the effect of exogenous CTRP3 (adenovirus or recombinant CTRP3) replenishment upon MI injury were investigated. MI significantly inhibited adipocyte CTRP3 expression and reduced plasma CTRP3 level, reaching nadir 3 days post-MI. CTRP3 replenishment improved survival rate (P<0.05), restored cardiac function, attenuated cardiomyocyte apoptosis, increased revascularization, and dramatically reduced interstitial fibrosis (P values all <0.01). CTRP3 replenishment had no significant effect upon cardiac AMP-activated protein kinase (AMPK) phosphorylation, but significantly increased Akt phosphorylation and expression of hypoxia inducing factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Surprisingly, treatment of human umbilical vascular endothelial cells (HUVECs) with CTRP3 did not directly affect nitric oxide production or tube formation. However, pre-conditioned medium from CTRP3-treated cardiomyocytes significantly enhanced HUVEC tube formation, an effect blocked by either pre-treatment of cardiomyocytes with a PI3K inhibitor, or pre-treatment of HUVECs with a VEGF inhibitor. Finally, protective effect of adipocytes conditioned medium against hypoxia-induced cardiomyocyte injury is significantly blunted when CTRP3 is knocked down.
Conclusions—CTRP3 is a novel anti-apoptotic, pro-angiogenic, and cardioprotective adipokine, whose expression is significantly inhibited following MI.
- Received February 14, 2012.
- Accepted April 24, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited