Regulatory role of ovarian sex hormones in calcium uptake activity of cardiac sarcoplasmic reticulum

Abstract

Alterations in the intracellular Ca2+ handling in cardiomyocytes may underlie the cardiac dysfunction observed in the ovarian sex hormone-deprived condition. To test the hypothesis that ovarian sex hormones had a significant role in the cardiac intracellular Ca2+ mobilization, the sarcoplasmic reticulum (SR) Ca2+ uptake and SR Ca2+-ATPase (SERCA) activity were determined in 10-wk ovariectomized rat hearts. With the use of left ventricular homogenate preparations, a significant suppression of maximum SR Ca2+ uptake activity, but with an increase in SR Ca2+ responsiveness, was demonstrated in ovariectomized hearts. In parallel measurements of SERCA activity in SR-enriched membrane preparations from ovariectomized hearts, a suppressed maximum SERCA activity with a leftward shift in the relationship between pCa (-log molar free Ca2+ concentration) and SERCA activity was also detected. A significant downregulation of SERCA proteins and reduction in the SERCA mRNA level were observed in association with suppressed maximum SERCA activity. While there were no changes in total phospholamban and phosphorylated Ser16 phospholamban levels, a decrease in phosphorylated Thr17 phospholamban as well as an increase in the suprainhibitory, monomeric form of phospholamban stoichiometry was found. Estrogen and progesterone supplementations were equally effective in preventing changes in ovariectomized hearts. Our data showed for the first time that female sex hormones played an important role in the regulation of the cardiac SR Ca2+ uptake. Under hormone-deficient conditions, there was an adaptive response of SERCA that escaped the regulatory effect of phospholamban.