Heart failure is accompanied by severely impaired Î²-adrenergic receptor (Î²AR) function, which includes loss of Î²AR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of Î²AR function is agonist-stimulated receptor phosphorylation by the Î²AR kinase (Î²ARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in Î²AR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of Î²ARK1 or the Î²2AR 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(-/-)/Î²2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP(-/-)/Î²ARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP(-/-)/Î²ARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP(-/-) mice but less than controls. Importantly, heightened Î²AR 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 Î²ARK1 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 Î²AR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit Î²ARK1 as a novel mode of therapy.
|Titolo:||Expression of a Î²-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice|
|Data di pubblicazione:||1998|
|Appare nelle tipologie:||1.1.1 Articolo su rivista con DOI|