C1q/Tumor Necrosis Factor–Related Protein-9, a Novel Adipocyte-Derived Cytokine, Attenuates Adverse Remodeling in the Ischemic Mouse Heart via Protein Kinase A Activation

Abstract

Background— C1q/tumor necrosis factor–related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. However, the role of CTRP9 in postmyocardial infarction remodeling remains completely unknown. This study determined whether CTRP9 may regulate cardiac remodeling after acute myocardial infarction (AMI) and elucidated the underlying mechanisms. Methods and Results— Male adult mice were subject to AMI by left anterior descending coronary artery ligation or sham surgery and treated with saline (vehicle) or globular CTRP9 via peritoneal implant osmotic pumps for 6 weeks. H9C2 cardiac cell lines were used in vitro for determining underlying mechanisms. Adipocyte CTRP9 expression and plasma CTRP9 levels were both significantly reduced after AMI. Compared with vehicle, CTRP9 treatment improved animal survival rate ( P <0.05), restored cardiac function ( P <0.05), attenuated adverse remodeling ( P <0.01), and ameliorated cardiomyocyte apoptosis and fibrosis after AMI ( P <0.01). Among the multiple antiremodeling molecules determined, AMP-activated protein kinase, protein kinase A (PKA), and Akt were significantly activated in CTRP9-treated heart. Surprisingly, CTRP9 remains cardioprotective in mice with cardiomyocyte-specific overexpression of a mutant AMP-activated protein kinase α2 subunit (AMPK-DN). Additional in vitro experiments demonstrated that administration of either PKA inhibitor or PKA-specific small interfering RNA virtually abolished the antiapoptotic effect of CTRP9 ( P <0.05), whereas inhibition of Akt is less effective in blocking CTRP9 cardioprotection. Finally, CTRP9 phosphorylates BCL-2-associated agonist of cell death at its multiple antiapoptotic sites, an effect blocked by PKA inhibitor. Conclusions— We demonstrate that adipokine CTRP9 attenuates adverse cardiac remodeling after AMI, largely via a PKA-dependent pathway.