Cardiac-directed overexpression of wild-type alpha(1B)-adrenergic receptorinduces dilated cardiomyopathy

Using transgenesis as a paradigm, we show here that alpha (1)-adrenergic re ceptors (alpha (1)AR) play an important role in cardiac homeostasis. Cardio myocyte-specific overexpression of the alpha (1B)AR subtype resulted in the development of dilated cardiomyopathy and death at similar to9 mo of age w ith typical signs of heart failure. Histological analyses showed the enlarg ement of all four cardiac chambers and cardiomyocyte disarray in the failin g hearts. Transgenic animals showed increased left ventricular areas, as as sessed by echocardiography. In addition, a progressive decrease in left ven tricular systolic function was revealed. The abundance and activity of sarc o( endo) plasmic reticulum Ca2+-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased. alpha -Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas beta -MHC wa s induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo , whereas atrial natriuretic factor mRNA was elevated at all times. This mo del mimics structural and functional features of idiopathic dilated cardiom yopathy. The results of this study suggest that chronic a1AR activity is de leterious for cardiac function.