Cardiac-directed overexpression of wild-type α1B-adrenergic receptor induces dilated cardiomyopathy

Abstract

Using transgenesis as a paradigm, we show here that α1-adrenergic receptors (α1AR) play an important role in cardiac homeostasis. Cardiomyocyte-specific overexpression of the α1BAR subtype resulted in the development of dilated cardiomyopathy and death at ∼9 mo of age with typical signs of heart failure. Histological analyses showed the enlargement of all four cardiac chambers and cardiomyocyte disarray in the failing hearts. Transgenic animals showed increased left ventricular areas, as assessed by echocardiography. In addition, a progressive decrease in left ventricular systolic function was revealed. The abundance and activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased. α-Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas β-MHC was induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo, whereas atrial natriuretic factor mRNA was elevated at all times. This model mimics structural and functional features of idiopathic dilated cardiomyopathy. The results of this study suggest that chronic α1AR activity is deleterious for cardiac function.