TARGETED ABLATION OF THE PHOSPHOLAMBAN GENE IS ASSOCIATED WITH MARKEDLY ENHANCED MYOCARDIAL-CONTRACTILITY AND LOSS OF BETA-AGONIST STIMULATION

Phospholamban is the regulator of the Ca2+ ATPase in cardiac sarcoplas mic reticulum (SR), and it has been suggested to be an important deter minant in the inotropic responses of the heart to beta-adrenergic stim ulation. To determine the role of phospholamban in vivo, the gene codi ng for this protein was targeted in murine embryonic stem cells, and m ice deficient in phospholamban were generated. The phospholamban-defic ient mice showed no gross developmental abnormalities but exhibited en hanced myocardial performance without changes in heart rate. The time to peak pressure and the time to half-relaxation were significantly sh orter in phospholamban-deficient mice compared with their wild-type ho mozygous littermates as assessed in work-performing mouse heart prepar ations under identical venous returns, afterloads, and heart rates. Th e first derivatives of intraventricular pressure (+/-dP/dt) were also significantly elevated, and this was associated with an increase in th e affinity of the SR Ca2+-ATPase for Ca2+ in the phospholamban-deficie nt hearts. Baseline levels of these parameters in the phospholamban-de ficient hearts were equal to those observed in hearts of wild-type lit termates maximally stimulated with the p-agonist isoproterenol. These findings indicate that phospholamban acts as a critical repressor of b asal myocardial contractility and may be the key phosphoprotein in med iating the heart's contractile responses to beta-adrenergic agonists.