Published Online
on January 24, 2005

A more recent version of this article appeared on February 8, 2005

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Submitted on February 12, 2004
Revised on April 22, 2004
Accepted on May 19, 2004

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

Hideo Tachibana MD, PhD, Sathyamangla V. Naga Prasad PhD, Robert J. Lefkowitz MD, Walter J. Koch PhD, and Howard A. Rockman MD^*

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.

^* To whom correspondence should be addressed. E-mail: h.rockman{at}duke.edu.

Background--Heart failure is characterized by abnormalities in -adrenergic receptor (AR) signaling, including increased level of myocardial AR kinase 1 (ARK1). Our previous studies have shown that inhibition of ARK1 with the use of the G sequestering peptide of ARK1 (ARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of ARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of ARK1 inhibition correlates with the degree of heart failure.

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

Conclusions--These data show that the level of ARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when ARK1 inhibition is considered as a molecular target.

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

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