EXPRESSION OF A BETA-ADRENERGIC-RECEPTOR KINASE-1 INHIBITOR PREVENTS THE DEVELOPMENT OF MYOCARDIAL FAILURE IN GENE-TARGETED MICE

Heart failure is accompanied by severely impaired beta-adrenergic rece ptor (beta AR) function, which includes loss of beta AR density and fu nctional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of beta AR function is agonist-stimulated r eceptor phosphorylation by the beta AR kinase (beta ARK1), an enzyme k nown to be elevated in failing human heart tissue. To investigate whet her alterations in beta AR function contribute to the development of m yocardial failure, transgenic mice with cardiac-restricted overexpress ion of either a peptide inhibitor of beta ARK1 or the beta(2)AR were m ated into a genetic model of murine heart failure (MLP-/-). In vivo ca rdiac function was assessed by echocardiography and cardiac catheteriz ation, Both MLP-/- and MLP-/-/beta(2)AR mice had enlarged left ventric ular (LV) chambers with significantly reduced fractional shortening an d mean velocity of circumferential fiber shortening. In contrast, MLP- /-/beta ARKct mice had normal LV chamber size and function, Basal LV c ontractility in the MLP-/-/beta ARKct mice, as measured by LV dP/dtmax , was increased significantly compared with the MLP-/- mice but less t han controls. Importantly, heightened beta AR desensitization in the M LP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), w as completely reversed with overexpression of the beta ARK1 inhibitor, We report here the striking finding that overexpression of this inhib itor prevents the development of cardiomyopathy in this murine model o f heart failure, These findings implicate abnormal beta AR-G protein c oupling in the pathogenesis of the failing heart and point the way tow ard development of agents to inhibit beta ARK1 as a novel mode of ther apy.