Beta1 and Beta2 adrenergic receptors are critical to heart function and disease. The modulation of the Beta adrenergic signaling system by """"""""Beta-blockers"""""""" is an important tool used in the treatment of heart disease. Studies in mice have demonstrated that by altering the density of Beta-adrenergic receptors, profound changes occur in cardiac function that have helped us to understand the Beta-AR's role in the heart. Interestingly, the effects of Beta1 overexpression have been detrimental while those of Beta2 largely beneficial in research animals. The reasons for the differential effects of the Beta-ARs are not well understood. Both ARs are able to stimulate adenylyl cyclase to increase chronotropy and inotropy. We think that there are areas of the proteins where the divergent animo acid sequences produce different patterns of regulation that explain these disparate effects in vivo. Our central hypothesis is that side by side adenoviral-mediated intracoronary gene delivery of Beta1 and Beta2-ARs to the rabbit hearts will produce different effects both in healthy rabbits and in a rabbit of HF. Furthermore, the overexpression of a chimeric protein that incorporates elements of both Beta1 and Beta2-ARs will allow a more detailed description of the regulated regions of the proteins that explain their divergent effects.
