Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.
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BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of betaARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart failure. METHODS AND RESULTS: Transgenic (TG) mice with varying degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial betaARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of betaARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low betaARKct expression developed severe heart failure, whereas mice with high betaARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in betaAR function, similar to the WT mice. CONCLUSIONS: These data show that the level of betaARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.
Cardiac Output, Low
Cyclic AMP-Dependent Protein Kinases
beta-Adrenergic Receptor Kinases
Published Version (Please cite this version)10.1161/01.CIR.0000142291.70954.DF
Publication InfoTachibana, Hideo; Naga Prasad, Sathyamangla V; Lefkowitz, Robert J; Koch, Walter J; & Rockman, Howard A (2005). Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure. Circulation, 111(5). pp. 591-597. 10.1161/01.CIR.0000142291.70954.DF. Retrieved from https://hdl.handle.net/10161/5908.
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James B. Duke Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively overexp
Alphabetical list of authors with Scholars@Duke profiles.