In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. 13 ( 2004-04-06), p. 1590-1593
Abstract:
Background— Failing human myocardium is characterized by an attenuated contractile response to β-adrenergic receptor (βAR) stimulation due to changes in this signaling cascade, including increased expression and activity of the β-adrenergic receptor kinase (βARK1). This leads to desensitization and downregulation of βARs. Previously, expression of a peptide inhibitor of βARK1 (βARKct) has proven beneficial in several animal models of heart failure (HF). Methods and Results— To test the hypothesis that inhibition of βARK1 could improve β-adrenergic signaling and contractile function in failing human myocytes, the βARKct was expressed via adenovirus-mediated (AdβARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. AdβARKct 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 AdβARKct-treated cells were increased in response to the β-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 AdβARKct-treated myocytes. Conclusions— These results demonstrate that as in animal models of HF, expression of the βARKct can improve contractile function and β-adrenergic responsiveness in failing human myocytes. Thus, βARK1 inhibition may represent a therapeutic strategy for human HF.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.0000125521.40985.28
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2004
detail.hit.zdb_id:
1466401-X
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