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Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function

Gene Therapy volume 6, pages 1298–1304 (1999)Cite this article

Abstract

Gene transfer to modify donor heart function during transplantation has significant therapeutic implications. Recent studies by our laboratory in transgenic mice have shown that overexpression of β2-adrenergic receptors (β2-ARs) leads to significantly enhanced cardiac function. Thus, we investigated the functional consequences of adenovirus-mediated gene transfer of the human β2-AR in a rat heterotopic heart transplant model. Donor hearts received 1 ml of solution containing 1 × 1010 p.f.u. of adenovirus encoding the β2-AR or an empty adenovirus as a control. Five days after transplantation, basal left ventricular (LV) pressure was measured using an isolated, isovolumic heart perfusion apparatus. A subset of hearts was stimulated with the β2-AR agonist, zinterol. Treatment with the β2-AR virus resulted in global myocardial gene transfer with a six-fold increase in mean β-AR density which corresponded to a significant increase in basal contractility (LV + dP/dtmax, control: 3152.1 ± 286 versus β2-AR, 6250.6* ± 432.5 mmHg/s; n = 10, *P < 0.02). β2-AR overexpressing hearts also had higher contractility after zinterol administration compared with control hearts. Our results indicate that myocardial function of the transplanted heart can be enhanced by the adenovirus-mediated delivery of β2-ARs. Thus, genetic manipulation may offer a novel therapeutic strategy to improve donor heart function in the post- operative setting.

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Acknowledgements

The authors wish to thank K Shotwell for assistance with biochemical assays and K Peppel for helpful discussions during the early phases of this study. We also thank the Genzyme Corporation (Framingham, MA, USA) for preparation and purification of some of the Adeno-β2AR used in this study. This work was supported in part by NIH grants HL-16037 (RJL), HL-59533 (WJK) and HL-56205 (WJK).

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    A P Kypson, S C Hendrickson, S A Akhter, R E Lilly, P C Dolber, D D Glower & W J Koch

  2. Department of Medicine, Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA

    K Wilson, P H McDonald & R J Lefkowitz

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  1. A P Kypson
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Kypson, A., Hendrickson, S., Akhter, S. et al. Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function. Gene Ther 6, 1298–1304 (1999). https://doi.org/10.1038/sj.gt.3300940

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