Dose dependent effects of cardiac β 2 adrenoceptor gene therapy

J. Mark Jones, Katrina H. Wilson, Charles Steenbergen, Walter J. Koch, Carmelo A. Milano

Research output: Contribution to journalArticlepeer-review

Abstract

Adenoviral-mediated gene transfer during cardiopulmonary bypass (CPB) achieves efficient myocardial transgene expression. The optimal vector dose required to produce not only increased β adrenoceptor (βAR) density but, more importantly, enhanced left ventricular (LV) function is unknown. In addition, it is unclear if absent extracardiac expression in preliminary studies represented cardiac specific, as opposed to selective gene delivery, as a consequence of low vector doses. Adenoviral vector encoding the human β 2 adrenoceptor (Adeno-β 2AR) was delivered to cardioplegic arrested hearts of neonatal piglets during CPB in three doses ranging from 5 × 10 11 total viral particles (tvp) to 2 × 10 12 tvp. Control animals received adenoviral vector encoding β galactosidase (Adeno-βgal) or PBS (PBS). LV and liver βAR density and in vivo LV function were assessed 5 days later. Elevated LV βAR density was present after delivery of Adeno-β 2AR at all doses. Piglets which received 5 × 10 11 tvp and 1 × 10 12 tvp Adeno-β 2AR demonstrated enhanced LV dP/dt max but in those receiving 2 × 10 12 tvp LV dP/dt max was unchanged. Moreover, at this higher dose of adenoviral vector the detrimental effects of cardiac inflammation and extracardiac gene overexpression became apparent. Although the highest increase in cardiac βAR density occurred after high-dose Adeno-β 2AR, LV dP/dt max was not enhanced. Moreover, significant extracardiac gene expression was present at this dose, emphasizing the need for careful dose response studies in gene therapy. However, cardiac selective β 2AR overexpression does occur following adenoviral vector delivery during CPB and cardioplegic arrest resulting in enhanced LV dP/dt max.

Original languageEnglish (US)
Pages (from-to)113-120
Number of pages8
JournalJournal of Surgical Research
Volume122
Issue number1
DOIs
StatePublished - Nov 2004
Externally publishedYes

Keywords

  • cardiopulmonary bypass
  • gene therapy
  • hemodynamics
  • surgery
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Surgery

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