MODULATION OF SERCA2 EXPRESSION BY THYROID-HORMONE AND NOREPINEPHRINEIN CARDIOCYTES - ROLE OF CONTRACTILITY

Decreased expression of the cardiac slow-twitch sarcoplasmic reticulum Ca2+- adenosinetriphosphatase (SERCA2), a major determinant of Ca2+ h omeostasis, contributes to the abnormal intracellular Ca2+ handling in the failing heart. We investigated the contractility dependence of th e effects of norepinephrine (NE) and thyroid hormone (T-3) On SERCA2 e xpression in cultured neonatal heart cells under serum-free conditions . NE and T-3 are associated with pathological and physiological forms of hypertrophy, respectively, whereas both hormones increase contracti lity. In contracting cultures, T-3 increased SERCA2 protein and mRNA l evels by 35 and 110%, respectively. The same stimulatory effects of T- 3 On SERCA2 expression were found in contraction-arrested cells. In co ntracting cultures, NE induced a decrease of SERCA2 protein and mRNA l evels by 40 and 60%, respectively. In contrast, SERCA2 protein and mRN A levels were not decreased by NE in contraction-arrested cells, indic ating that contractility is a prerequisite for the negative influence of NE on SERCA2 expression. Electrical stimulation at a fixed frequenc y in the presence and absence of NE demonstrated that the NE-induced i ncrease in contraction frequency is unlikely to account for the decrea sed SERCA2 expression induced by NE. The results suggest that the effe ct of contractility on SERCA2 expression depends on the signal transdu ction pathways that are activated by NE and T-3.