期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：12
页码：7000-7005
DOI：10.1073/pnas.95.12.7000
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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}2AR 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}2AR 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.
