Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice

Heart failure is accompanied by severely impaired beta-adrenergic receptor (beta AR) function, which includes loss of beta AR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of beta AR function is agonist-stimulated receptor phosphorylation by the beta AR kinase (beta ARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in beta AR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of beta ARK1 or the beta(2)AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization, Both MLP-/- and MLP-/-/beta(2)AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/beta ARKct mice had normal LV chamber size and function, Basal LV contractility in the MLP-/-/beta ARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened beta AR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the beta ARK1 inhibitor, We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure, These findings implicate abnormal beta AR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit beta ARK1 as a novel mode of therapy.