Potentiation of β-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes

Mark H. Drazner, Karsten C. Peppel, Sara Dyer, Augustus O. Grant, Walter J. Koch, Robert J. Lefkowitz

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Our laboratory has been testing the hypothesis that genetic modulation of the β-adrenergic signaling cascade can enhance cardiac function. We have previously shown that transgenic mice with cardiac overexpression of either the human β2-adrenergic receptor (β2AR) or an inhibitor of the β- adrenergic receptor kinase (βARK), an enzyme that phosphorylates and uncouples agonist-bound receptors, have increased myocardial inotropy. We now have created recombinant adenoviruses encoding either the β2AR (Adeno- β2AR) or a peptide βARK inhibitor (consisting of the carboxyl terminus of βARK1, Adeno-βARKct) and tested their ability to potentiate β-adrenergic signaling in cultured adult rabbit ventricular myocytes. As assessed by radioligand binding, Adeno-β2AR infection led to ~20-fold over-expression of β-adrenergic receptors. Protein immunoblots demonstrated the presence of the Adeno-βARKct transgene. Both transgenes significantly increased isoproterenol-stimulated cAMP as compared to myocytes infected with an adenovirus encoding β-galactosidase (Adeno-βGal) but did not affect the sarcolemmal adenylyl cyclase response to Forskolin or NaF. β-Adrenergic agonist-induced desensitization was significantly inhibited in Adeno-βARKct- infected myocytes (16±2%) as compared to Adeno-βGal-infected myocytes (37±1%, P < 0.001). We conclude that recombinant adenoviral gene transfer of the β2AR or an inhibitor of βARK-mediated desensitization can potentiate β-adrenergic signaling.

Original languageEnglish (US)
Pages (from-to)288-296
Number of pages9
JournalJournal of Clinical Investigation
Volume99
Issue number2
DOIs
StatePublished - Jan 15 1997

Keywords

  • congestive heart failure
  • cultured cells
  • gene therapy
  • myocardium
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Medicine(all)

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