Abstract 8965: C1q/TNF-Related Protein-3, a Newly Identified Adipokine, is a Novel Anti-Apoptotic, Pro-Angiogenic, and Cardioprotective Molecule in the Ischemic Mouse Heart
Obesity/diabetes adversely affects ischemic heart remodeling via incompletely understood mechanisms. Adipocytes produce various adipokines. Delineating these adipokines’ cardiovascular profiles is critical in advancing our knowledge regarding how obesity/diabetes may cause cardiovascular damage. C1q/TNF-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation. However, the cardiovascular actions of this novel adipokine remain unknown. The current study determined whether CTRP3 may regulate post-ischemic cardiac remodeling and cardiac dysfunction, and, if so, sought to elucidate the involved underlying mechanisms. Male adult mice were subjected to MI, and treated with saline or CTRP3 via peritoneally implanted osmotic-pumps for 2 weeks. Plasma CTRP3 levels were significantly reduced 4 hours after MI, and remained at low level until 1 week after MI. Supplementation of CTRP3 (beginning 4 hours after MI) at a dose (0.25 μg/g/day) restoring physiological CTRP3 levels in MI animals improved survival rate (P<0.05), rescued cardiac function (determined by echocardiograph and left ventricular catheterization, P<0.01), attenuated cardiomyocyte apoptosis within infarct border zones (determined by TUNEL staining and caspase 3 activation, P<0.01), increased revascularization (evidenced by CD31 and α-SMA immunostaining, P<0.01), and dramatically reduced interstitial fibrosis (41% reduction vs. vehicle group, P<0.01). In vivo CTRP3 administration had no significant effect upon AMPK phosphorylation, but significantly increased Akt phosphorylation, and increased HIF-1α and VEGF expression. Surprisingly, treatment of HUVECs in vitro with CTRP3 failed to increase tube formation. However, pre-conditioned medium from CTRP3-treated cardiomyocytes significantly enhanced HUVEC tube formation, an effect that was blocked by either pre-treatment of cardiomyocytes with a PI3K inhibitor, or pre-treatment of HUVECs with a VEGF inhibitor. Our results demonstrate for the first time that CTRP3 is a novel anti-apoptotic, pro-angiogenic, and cardioprotective adipokine in the ischemic mouse heart, via facilitation of cardiomyocyte-endothelium communication.
- © 2011 by American Heart Association, Inc.