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(Circulation. 2005;111:591-597.)
© 2005 American Heart Association, Inc.

Heart Failure

Level of ß-Adrenergic Receptor Kinase 1 Inhibition Determines Degree of Cardiac Dysfunction After Chronic Pressure Overload–Induced Heart Failure

From the Departments of Medicine (H.T., S.V.N.P., R.J.L., H.A.R.), Cell Biology (H.A.R.), Molecular Genetics (H.A.R.), and Surgery (W.J.K.), and the Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC. Dr Koch is now at the Center for Translational Medicine, Jefferson Medical College, Philadelphia, Pa.

Correspondence to Howard A. Rockman, MD, Duke University Medical Center, Research Dr, DUMC 3104, Durham, NC 27710. E-mail h.rockman{at}duke.edu

Received February 12, 2004; revision received April 22, 2004; accepted May 19, 2004.

Background— Heart failure is characterized by abnormalities in ß-adrenergic receptor (ßAR) signaling, including increased level of myocardial ßAR kinase 1 (ßARK1). Our previous studies have shown that inhibition of ßARK1 with the use of the Gß sequestering peptide of ßARK1 (ßARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of ßARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of ßARK1 inhibition correlates with the degree of heart failure.

Methods and Results— Transgenic (TG) mice with varying degrees of cardiac-specific expression of ßARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial ßARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of ßARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low ßARKct expression developed severe heart failure, whereas mice with high ßARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of ßARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal ßAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in ßAR function, similar to the WT mice.

Conclusions— These data show that the level of ßARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when ßARK1 inhibition is considered as a molecular target.

Key Words: receptors, adrenergic, beta • heart failure • signal transduction • mice, transgenic • gene therapy

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