Abstract 10958: C1q/TNF-Related Protein-9, a Novel Adipocyte-Derived Cytokine, Attenuates Adverse Remodeling in the Ischemic Mouse Heart via PKA Activation
C1q/TNF-related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic-regulatory properties. However, the role of CTRP9 in post-MI remodeling remains completely unknown. The aims of the current study were 1) to detect whether CTRP9 levels change after acute MI (AMI); 2) to determine the effects of exogenous CTRP9 supplementation upon post-ischemic cardiac remodeling and dysfunction; and 3) to elucidate the mechanisms responsible for CTRP's effects upon cardiac function. Male adult mice were subject to permanent left anterior descending (LAD) artery ligation or sham surgery, and treated with saline (vehicle) or CTRP9 (beginning 4 hours post-MI) via peritoneally-implanted osmotic-pumps for 6 weeks. Both adipose CTRP9 mRNA and plasma CTRP9 levels decreased 1 day after AMI, reaching nadir 3 days post-MI, and gradually increasing to baseline thereafter. To determine the pathological significance of AMI inhibition of CTRP9 expression/production, exogenous CTRP9 was supplemented at dosage restoring plasma CTRP9 to control levels. Compared to vehicle, CTRP9 treatment improved animal survival rate (6 weeks post-MI, P>0.05), restored cardiac function (LVES, LVEDP, dP/dtmax, P>0.05), attenuated adverse remodeling (LV mass and LVEDD, P>0.01), and ameliorated cardiomyocyte apoptosis and fibrosis following AMI (P>0.01). Among multiple anti-remodeling molecules assayed, AMP-activated protein kinase (AMPK), protein kinase-A (PKA), and Akt were significantly activated in the CTRP9-treated heart. Surprisingly, the cardioprotective effect of CTRP9 is only slightly attenuated during AMPK inhibition, and CTRP9 remains cardioprotective in cardiac-specific AMPK-DN mice (P>0.01 vs. vehicle). However, PKA inhibition via pharmaco-inhibitor or PKA-specific siRNA knockdown virtually abolished CTRP9's cardioprotective effects, whereas Akt inhibition only modestly affected CTRP9-mediated cardioprotection. Finally, CTRP9 phosphorylates BAD at its multiple anti-apoptotic sites, an effect blocked by inhibition of PKA, but not AMPK or Akt. We demonstrate for the first time that adipokine CTRP9 attenuates adverse cardiac remodeling following AMI, largely via a PKA-dependent pathway.
- © 2012 by American Heart Association, Inc.