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

Abstract

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 CTRP 9 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 CTRP 9 were detected using ELISA . The results revealed that CTRP 9 levels in β 1 ‐ AA –positive patients were lower than those in β 1 ‐ AA –negative patients, and serum CTRP 9 concentrations were inversely correlated with β 1 ‐ AA . β 1 ‐ AA monoclonal antibodies (β 1 ‐ 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 β 1 ‐ AA mAb–treated mice. Moreover, compared with the β 1 ‐ 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 β 1 ‐AAmAb. Conclusions This study provides the first evidence that the long‐term existence of β 1 ‐ 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 β 1 ‐ AA –positive patients with coronary heart disease.