Heart failure is characterized by a number of abnormalities at the cellular level in the various steps of excitation-contraction coupling. One of the key abnormalities in both human and experimental heart failure is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handling. Deficient SR Ca2+ uptake during relaxation has been identified in hypertrophied and failing hearts from both human and animal models and has been associated with a decrease in the expression and activity of SR Ca2+-ATPase. Recently, adenovirus vectors have been shown to be efficient in transferring exogenous genes into myocardial cells. Using replication-deficient recombinant adenoviral vectors, the applicant plans to introduce the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene directly into rats with pressure-overload induced heart failure which are known to have a decrease in SERCA2a expression. The applicant will validate the use of adenoviral gene transfer in the rat model of heart failure and will test the hypothesis that increasing the expression of SERCA2a will restore contractility and normalize intracellular calcium cycling in this model of heart failure.
