title: Adenovirus-mediated gene transfer of the beta2-adrenergic receptor to donor hearts enhances cardiac function.
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 beta2-adrenergic receptors (beta2-ARs) leads to significantly enhanced cardiac function. Thus, we investigated the functional consequences of adenovirus-mediated gene transfer of the human beta2-AR in a rat heterotopic heart transplant model. Donor hearts received 1 ml of solution containing 1 x 1010 p.f.u. of adenovirus encoding the beta2-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 beta2-AR agonist, zinterol. Treatment with the beta2-AR virus resulted in global myocardial gene transfer with a six-fold increase in mean beta-AR density which corresponded to a significant increase in basal contractility (LV + dP/dtmax, control: 3152.1 +/- 286 versus beta2-AR, 6250.6* +/- 432.5 mmHg/s; n = 10, *P < 0.02). beta2-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 beta2-ARs. Thus, genetic manipulation may offer a novel therapeutic strategy to improve donor heart function in the post- operative setting.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kypson
authors.forename: S
authors.initials: S
authors.lastname: Hendrickson
authors.forename: S
authors.initials: S
authors.lastname: Akhter
authors.forename: K
authors.initials: K
authors.lastname: Wilson
authors.forename: P
authors.initials: P
authors.lastname: McDonald
authors.forename: R
authors.initials: R
authors.lastname: Lilly
authors.forename: P
authors.initials: P
authors.lastname: Dolber
authors.forename: D
authors.initials: D
authors.lastname: Glower
authors.forename: R
authors.initials: R
authors.lastname: Lefkowitz
authors.forename: W
authors.initials: W
authors.lastname: Koch
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D016027:Heart Transplantation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D020332:Rats, Inbred LEC; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*
chemical_list: D018343:Receptors, Adrenergic, beta-2