Autoantibodies Against β(1)‐Adrenoceptor Exaggerated Ventricular Remodeling by Inhibiting CTRP9 Expression

BACKGROUND: Autoantibodies against the second extracellular loop of the β(1)‐adrenoceptor (β(1)‐AA) act similarly to agonist of β(1)‐adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor–related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP9 in ventricular remodeling induced by β(1)‐AA. METHODS AND RESULTS: Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of β(1)‐AA and CTRP9 were detected using ELISA. The results revealed that CTRP9 levels in β(1)‐AA–positive patients were lower than those in β(1)‐AA–negative patients, and serum CTRP9 concentrations were inversely correlated with β(1)‐AA. β(1)‐AA monoclonal antibodies (β(1)‐AAmAbs) were administered in mice with and without rAAV9‐cTnT‐Full Ctrp9‐FLAG virus for 8 weeks. Reverse transcription–polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP9 expression was significantly reduced in β(1)‐AAmAb–treated mice. Moreover, compared with the β(1)‐AAmAb alone group, cardiac‐specific CTRP9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP9 overexpression decreased the levels of G‐protein–coupled receptor kinase 2 and promoted the activation of AMP‐dependent kinase pathway. However, cardiac‐specific overexpression of CTRP9 had no effect on the levels of cAMP and protein kinase A activity elevated by β(1)‐AAmAb. CONCLUSIONS: This study provides the first evidence that the long‐term existence of β(1)‐AAmAb suppresses cardiac CTRP9 expression and exaggerates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in β(1)‐AA–positive patients with coronary heart disease.