CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts.

Abstract

Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-β1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-β1-induced Smad3 activation. CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.