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 phosphola mban protein levels and their regulatory effect on sarcoplasmic reticu lum (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 hyp erthyroidism these parameters were elevated compared with values for e uthyroid 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 hyperth yroid hearts, respectively. The relative tissue level of phospholamban was increased (135%) in hypothyroidism and decreased (75%) in hyperth yroidism compared with euthyroidism (100%). An opposite trend was obse rved 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 hypothyr oid and lowest in hyperthyroid hearts, and these changes correlated wi th changes in the EC(50) of the SR Ca2+ uptake for Ca2+. Stimulation o f hearts with 0.1 mu mol/L isoproterenol revealed that the relaxant ef fects were lower in hyperthyroid hearts and higher in hypothyroid hear ts compared with euthyroid hearts, consistent with the alterations in the phospholamban levels. The maximal increases in the speed of relaxa tion, elicited by isoproterenol stimulation, correlated with the chang es in the relative ratio of phospholamban to Ca2+-ATPase in these hear ts. These findings indicate that alterations in phospholamban levels a ssociated with various thyroid states may reflect alterations in (1) S R Ca2+ uptake rates, (2) the affinity of the SR Ca2+ pump for Ca2+, (3 ) the speed of relaxation of the myocardium, and (4) stimulatory effec ts by beta-adrenergic agonists.