Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts.
BACKGROUND: Failing human myocardium is characterized by an attenuated contractile response to beta-adrenergic receptor (betaAR) stimulation due to changes in this signaling cascade, including increased expression and activity of the beta-adrenergic receptor kinase (betaARK1). This leads to desensitization and downregulation of betaARs. Previously, expression of a peptide inhibitor of betaARK1 (betaARKct) has proven beneficial in several animal models of heart failure (HF). METHODS AND RESULTS: To test the hypothesis that inhibition of betaARK1 could improve beta-adrenergic signaling and contractile function in failing human myocytes, the betaARKct was expressed via adenovirus-mediated (AdbetaARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. AdbetaARKct 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 AdbetaARKct-treated cells were increased in response to the beta-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 AdbetaARKct-treated myocytes. CONCLUSIONS: These results demonstrate that as in animal models of HF, expression of the betaARKct can improve contractile function and beta-adrenergic responsiveness in failing human myocytes. Thus, betaARK1 inhibition may represent a therapeutic strategy for human HF.
Williams, ML; Hata, JA; Schroder, J; Rampersaud, E; Petrofski, J; Jakoi, A; Milano, CA; Koch, WJ
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