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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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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DOI: https://doi.org/10.1038/sj.gt.3300940
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