Published Online
on March 29, 2004

A more recent version of this article appeared on April 6, 2004

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Submitted on December 16, 2003
Revised on February 12, 2004
Accepted on February 18, 2004

Targeted -Adrenergic Receptor Kinase (ARK1) Inhibition by Gene Transfer in Failing Human Hearts

Matthew L. Williams MD, Jonathan A. Hata MD, Jacob Schroder MD, Edward Rampersaud MD, Jason Petrofski MD, Andre Jakoi BS, Carmelo A. Milano MD, and Walter J. Koch PhD^*

From the Department of Surgery, Duke University Medical Center (M.L.W., J.A.H., J.S., E.R., J.P., A.J., C.A.M., W.J.K.), Durham, NC; Department of Surgery, Massachusetts General Hospital (M.L.W.), Boston, Mass; and Center for Translational Medicine (W.J.K.), Thomas Jefferson University, Philadelphia, Pa.

^* To whom correspondence should be addressed. E-mail: walter.koch{at}jefferson.edu.

Background--Failing human myocardium is characterized by an attenuated contractile response to -adrenergic receptor (AR) stimulation due to changes in this signaling cascade, including increased expression and activity of the -adrenergic receptor kinase (ARK1). This leads to desensitization and downregulation of ARs. Previously, expression of a peptide inhibitor of ARK1 (ARKct) has proven beneficial in several animal models of heart failure (HF).

Methods and Results--To test the hypothesis that inhibition of ARK1 could improve -adrenergic signaling and contractile function in failing human myocytes, the ARKct was expressed via adenovirus-mediated (AdARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. AdARKct also contained the marker gene, green fluorescent protein, and successful gene transfer was confirmed via fluorescence and immunoblotting. Compared with uninfected failing myocytes (control), the velocities of both contraction and relaxation in the AdARKct-treated cells were increased in response to the -agonist isoproterenol (contraction: 57.5±6.6% versus 37.0±4.2% shortening per second, P<0.05; relaxation: 43.8±5.5% versus 27.5±3.9% lengthening per second, P<0.05). Fractional shortening was similarly enhanced (12.2±1.2% versus 8.0±0.9%, P<0.05). Finally, adenylyl cyclase activity in response to isoproterenol was also increased in AdARKct-treated myocytes.

Conclusions--These results demonstrate that as in animal models of HF, expression of the ARKct can improve contractile function and -adrenergic responsiveness in failing human myocytes. Thus, ARK1 inhibition may represent a therapeutic strategy for human HF.

Key words: myocytes • heart failure • gene therapy

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