Adenovirus-mediated gene transfer of the beta2-adrenergic receptor to donor hearts enhances cardiac function.
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.
Kypson
A
A
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Hendrickson
S
S
Akhter
S
S
Wilson
K
K
McDonald
P
P
Lilly
R
R
Dolber
P
P
Glower
D
D
Lefkowitz
R
R
Koch
W
W
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*
D018343:Receptors, Adrenergic, beta-2