Autoantibodies Against β₁-Adrenoceptor Exaggerated Ventricular Remodeling by Inhibiting CTRP9 Expression

Background Autoantibodies against the second extracellular loop of the β₁-adrenoceptor (β₁- AA ) act similarly to agonist of β₁-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 CTRP 9 in ventricular remodeling induced by β₁- AA . Methods and Results Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of β₁- AA and CTRP 9 were detected using ELISA . The results revealed that CTRP 9 levels in β₁- AA -positive patients were lower than those in β₁- AA -negative patients, and serum CTRP 9 concentrations were inversely correlated with β₁- AA . β₁- AA monoclonal antibodies (β₁- AA mAbs) were administered in mice with and without rAAV 9- cTnT -Full Ctrp9- FLAG virus for 8 weeks. Reverse transcription-polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP 9 expression was significantly reduced in β₁- AA mAb-treated mice. Moreover, compared with the β₁- AA mAb alone group, cardiac-specific CTRP 9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP 9 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 CTRP 9 had no effect on the levels of  cAMP and protein kinase A activity elevated by β₁-AAmAb. Conclusions This study provides the first evidence that the long-term existence of β₁- AA mAb suppresses cardiac CTRP 9 expression and exaggerates cardiac remodeling, suggesting that CTRP 9 may be a novel therapeutic target against pathologic remodeling in β₁- AA -positive patients with coronary heart disease.