Potentiation of β-adrenergic signaling by gene transfer

M. H. Drazner, W. J. Koch, R. J. Lefkowitz

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The β-adrenergic signaling cascade is an important regulator of myocardial function. Numerous abnormalities occur in this pathway and are associated with impaired cardiac contractility in patients with congestive heart failure (CHF). These signaling defects include downregulation of β- adrenergic receptors (βARs) and increased levels of β-adrenergic receptor kinase (βARK), an enzyme that phosphorylates and uncouples only agonist- bound receptors. Our laboratory has been testing the hypothesis that reversal of these β-adrenergic defects may be able to restore cardiac inotropy to normal in patients with depressed systolic function. Transgenic mice with cardiac overexpression of β2ARs or an inhibitor of βARK have enhanced cardiac function as compared to wild type littermates. Adenoviral vectors encoding the β2AR or βARK inhibitor potentiate βAR signaling in cultured adult rabbit ventricular myocytes. However, a controversy has developed in the literature regarding whether increasing β-adrenergic signaling would be beneficial or detrimental for patients with CHF. Those cautioning against this approach note that increased sympathetic activity is dangerous in CHF. Elevated catecholamine levels predict mortality and β-agonists are not beneficial for survival, while recent studies suggest that β-antagonists do improve outcome. Supporting these concerns is the demonstration that transgenic mice with cardiac overexpression of G(sα) and enhanced myocardial responsiveness to isoproterenol develop myocardial fibrosis. This article summarizes this controversy; highlights important differences between overexpression of βARs or a βARK inhibitor, overexpression of G(sα), and administration of β-agonists: and develops the hypothesis that these strategies may differ in their therapeutic efficacy in treating CHF.

Original languageEnglish (US)
Pages (from-to)220-227
Number of pages8
JournalProceedings of the Association of American Physicians
Volume109
Issue number3
StatePublished - May 28 1997

Keywords

  • adenovirus
  • gene therapy
  • heart failure
  • transgenic mice
  • β-adrenergic receptor kinase

ASJC Scopus subject areas

  • Medicine(all)

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