THYROID HORMONE-INDUCED ALTERATIONS IN PHOSPHOLAMBAN PROTEIN EXPRESSION - REGULATORY EFFECTS ON SARCOPLASMIC-RETICULUM CA2+ TRANSPORT AND MYOCARDIAL RELAXATION

The aim of the present study was to determine the changes in phospholamban protein levels and their regulatory effect on sarcoplasmic reticulum (SR) Ca2+ uptake and left ventricular function in hypothyroid and hyperthyroid rat hearts. Hypothyroidism was associated with decreases in basal left ventricular function (+dP/dt and -dP/dt), whereas in hyperthyroidism these parameters were elevated compared with values for euthyroid hearts. The maximal SR Ca2+ uptake rates were 12.8+/-1.1, 15.5+/-1.2, and 21.4+/-1.4 nmol Ca2+ per milligram per minute, and the EC(50) values for Ca2+ were 0.76+/-0.09, O.41+/-0.07, and 0.30+/-0.05 mu mol/L assayed in homogenates from hypothyroid, euthyroid, and hyperthyroid hearts, respectively. The relative tissue level of phospholamban was increased (135%) in hypothyroidism and decreased (75%) in hyperthyroidism compared with euthyroidism (100%). An opposite trend was observed for the SR Ca2+ ATPase, which was depressed (74%) in hypothyroid hearts but increased (134%) in hyperthyroid hearts. Consequently, the relative ratio of phospholamban to Ca2+-ATPase was highest in hypothyroid and lowest in hyperthyroid hearts, and these changes correlated with changes in the EC(50) of the SR Ca2+ uptake for Ca2+. Stimulation of hearts with 0.1 mu mol/L isoproterenol revealed that the relaxant effects were lower in hyperthyroid hearts and higher in hypothyroid hearts compared with euthyroid hearts, consistent with the alterations in the phospholamban levels. The maximal increases in the speed of relaxation, elicited by isoproterenol stimulation, correlated with the changes in the relative ratio of phospholamban to Ca2+-ATPase in these hearts. These findings indicate that alterations in phospholamban levels associated with various thyroid states may reflect alterations in (1) SR Ca2+ uptake rates, (2) the affinity of the SR Ca2+ pump for Ca2+, (3) the speed of relaxation of the myocardium, and (4) stimulatory effects by beta-adrenergic agonists.