부산대학교 도서관

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].sub.2]AR were mated into a genetic model of murine heart failure ([MLP.sup.-/-]). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both [MLP.sup.-/-] and [MLP.sup.-/-]/[[Beta].sub.2]AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, [MLP.sup.-/-]/[Beta]ARKct mice had normal LV chamber size and function. Basal LV contractility in the [MLP.sup.-/-]/[Beta]ARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the [MLP.sup.-/-] mice but less than controls. Importantly, heightened [Beta]AR desensitization in the [MLP.sup.-/-] 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.