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

Abstract

Bupharesponsiveness, 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 Ca 2ϩ 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 Ser 16 phospholamban levels, a decrease in phosphorylated Thr 17 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 Ca 2ϩ uptake. Under hormone-deficient conditions, there was an adaptive response of SERCA that escaped the regulatory effect of phospholamban. sarcoplasmic reticulum Ca 2ϩ -adenosine 5Ј-triphosphate activity; phospholamban; phosphorylation THE CARDIOREGULATORY ROLE of female sex hormones in contractile activity has been raised in many studies (23, 24, 28, 34 -36). Expression of both estrogen and progesterone receptors in myocytes indicated a direct effect of the hormones on myocardial function (14, 18). Studies of postmenopausal women using echocardiography have demonstrated significant decreases in cardiac contractility compared with those of premenopausal women (23,24). Reductions in stroke work and fractional shortening have also been demonstrated in studies using whole heart preparations of ovariectomized rats (28). In addition, suppression of both myosin ATPase activity and maximum myofibrillar ATPase activity with an upregulation of ␤-myosin heavy chain in ovariectomized rat hearts was reported (28,34,35). All evidence indicated important roles of female sex hormones in myocardial activation. The striking finding was an increase in the Ca 2ϩ responsiveness of cardiac myofilament activation with almost the same magnitude in ovariectomized hearts as that in cardiomyopathic failing hearts (17,34,35,38,39). The information thus implied a potential of cardiomyopathic induction by female sex hormone deficiency. It was, however, not known how myofilament Ca 2ϩ hypersensitivity was induced in the hormone-deficient heart. A reasonable hypothesis was that this effect may be an adaptive response of the heart to changes in the intracellular free Ca 2ϩ

Progesterone modulates SERCA2a expression and function in rabbit cardiomyocytes

“…Here we attempted to decipher the molecular mechanism of SERCA2a regulation by progesterone at the cellular level. We also observed a moderate 1.5-fold increase in SERCA2a protein levels in NRbCM, which is consistent with our findings and those of other researchers (4). This increase in SERCA2a protein levels was not associated with changes in mRNA levels, suggesting that the effect of progesterone is posttranslational.…”

“…Furthermore, supplementation with estrogen and progesterone restored SERCA2a mRNA levels, protein expression levels, and pump function (4). Recently, our laboratory showed that SERCA2a protein levels were moderately upregulated in progesterone-treated ovariectomized transgenic female LQT2 rabbits (20).…”

Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity

“…We (6,7) have previously demonstrated that chronic deprivation of female sex hormones induces a suppression in intracellular Ca 2ϩ transients together with a decrease in SERCA activity. Interestingly, in the present study, maximum SERCA activity of the heart of male sham rats was similar to that detected in ovariectomized rats (6), suggesting a lower SERCA activity in the male heart than in the female heart during young age.…”

“…SR membrane vesicles were prepared from left ventricular homogenates as previously described (6). In brief, the left ventricle was minced and homogenized in iced-cold 10 mM NaHCO 3 buffer (pH 6.8) containing a cocktail of protease inhibitors.…”

Takotsubo Cardiomyopathy

“…Estrogen receptors are expressed on cardiomyocytes (82), thus cardiomyocyte function could be directly affected by estrogen levels. Estrogen has also been shown to significantly suppress SERCA2 expression in ovariectomized rats compared to controls, thus altering cardiac myocyte sarcoplasmic reticulum calcium uptake (83). In the latter study, investigators noted that estrogen and progesterone supplementations were equally effective in preventing changes in ovariectomized hearts.…”