TY - JOUR
T1 - Dose dependent effects of cardiac β 2 adrenoceptor gene therapy
AU - Jones, J. Mark
AU - Wilson, Katrina H.
AU - Steenbergen, Charles
AU - Koch, Walter J.
AU - Milano, Carmelo A.
N1 - Funding Information:
We thank Dr. Robert J. Lefkowitz for helpful discussions throughout these studies. George Quick, Ronnie Johnston and Kurt Campbell provided technical assistance. This work was supported in part by National Institutes of Health grants HL 56205 (W.J.K.) and HL 59533 (W.J.K.), and the American Heart Association Grant-in-aid (C.A.M.).
Funding Information:
This work was supported in part by National Institutes of Health grants HL 56205 (W.J.K.) and HL 59533 (W.J.K.), and the American Heart Association Grant-in-aid (C.A.M.).
PY - 2004/11
Y1 - 2004/11
N2 - 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.
AB - 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.
KW - cardiopulmonary bypass
KW - gene therapy
KW - hemodynamics
KW - surgery
KW - β-adrenergic receptor
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U2 - 10.1016/j.jss.2004.06.009
DO - 10.1016/j.jss.2004.06.009
M3 - Article
C2 - 15522323
AN - SCOPUS:7444222294
SN - 0022-4804
VL - 122
SP - 113
EP - 120
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -