Adenovirus-mediated genetic manipulation of the myocardial beta-adrenergicsignaling system in transplanted hearts

Objectives: Ex vivo perfusion of the cardiac allograft during organ procure ment is an ideal environment for adenoviral vectors with transgenes that ta rget improving graft contractility. One such target is the beta-adrenergic receptor-signaiing system, in which alterations in transgenic mice have elu cidated novel means to improve the function of the heart in vivo. The purpo se of the current study was to determine the functional consequences of bet a-adrenergic receptor manipulation in a rabbit model of cardiac allograft t ransplantation. Methods: New Zealand White rabbits weighing 3 kg served as recipients to l- kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 ade noviral constructs was administered into the aortic root perfusing the graf t. Transgenes delivered encoded either the human beta(2)-adrenergic recepto r, a peptide inhibitor of beta-adrenergic receptor densensitization, or the marker transgene beta-galactosidase, Results: Five days after cervical heterotopic transplantation, left ventric ular performance was measured on a Langendorff apparatus. A moderate patter n of rejection was seen in all grafts. Biventricular myocyte expression of beta-galactosidase was observed, and beta(2)-adrenergic receptor density wa s elevated 10-fold in grafts that received adeno-beta(2)-adrenergic recepto r. Left ventricular systolic and diastolic performance was significantly in creased in grafts transfected with either adeno-beta(2)-adrenergic receptor or adeno-beta-adrenergic receptor densensitization compared with control g rafts that received adeno-beta-galactosidase. Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rab bit allograft model and, more important, genetic manipulation of beta-adren ergic receptor signaling either by increasing beta(2)-adrenergic receptor d ensity or blocking endogenous receptor desensitization improves graft funct ion acutely in this allograft model.