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Title: IMPACT OF ESTROGEN REPLACEMENT ON VENTRICULAR MYOCYTE CONTRACTILE FUNCTION AND PROTEIN KINASE B/AKT ACTIVATION

Author
item REN, JUN - UNIV OF WYOMING
item HINTZ, KADON - UNIV OF NORTH DAKOTA
item Roughead, Zamzam
item DUAN, JINHONG - UNIV OF WYOMING
item COLLIGAN, PETER - UNIV OF NORTH DAKOTA
item REN, BONNIE - UNIV OF WYOMING
item LEE, KAP - UNIV OF NORTH DAKOTA
item Zeng, Huawei

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/7/2003
Publication Date: 5/1/2003
Citation: Ren, J., Kinze, K., Roughead, Z.K., Duan, J., Colligan, P.B., Ren, B.H., Lee, K.J., Zeng, H. 2003. Impact of estrogren replacement on ventricular myocyte contractile function and protein kinase B/AKT activation. American Journal of Physiology. 284:H1800-H1807.

Interpretive Summary: Women with functional ovaries have a lower risk of cardiovascular disease than men and postmenopausal women. However, the mechanism by which the loss of ovarian function and estrogen replacement therapy affect cardiovascular health in women is not known. This study was designed to examine the effects of ovarian hormone deficiency and estrogen replacement on heart function. Mature female rats were either ovariectomized (Ovx) or sham-operated (Sham). To simulate estrogen replacement therapy in postmenopausal women, a subgroup of the Ovx rats received estrogen replacement for 8 weeks. Several characteristics of heart muscle function were evaluated including the mechanical properties (such as the contractility of the muscle cells) and certain important enzymes for heart function (called Ca2+-ATPase and PKB/Akt). We found that removing the ovaries caused a reduction in serum estrogen levels and the size of the uterus, but an increase in body weights. All of these changes were abolished by estrogen replacement. The removal of the ovaries also affected the contractility of the heart muscle cells; this was also restored by estrogen replacement. Our findings suggest that both mechanical and protein functions of heart muscles (ventricular myocytes) are directly regulated by the presence of ovarian hormones, especially estrogen. These findings will be useful for scientists and health-care people who are studying cardiovascular health.

Technical Abstract: Women with functional ovaries have a lower cardiovascular risk than age-matched men and postmenopausal women. However, estrogen replacement therapy remains controversial. The present study was designed to examine the effect of ovarian hormone deficiency and estrogen replacement on ventricular myocyte contractile function and protein kinase B (PKB)/Akt activation. Mature nulliparous female rats were subjected to bilateral ovariectomy (Ovx) or sham-operation (Sham). A subgroup of Ovx rats received estrogen (E2) replacement (40 ug/kg/d, i.p.) for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in ventricular myocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt), intracellular Ca2+ fura-2 fluorescence intensity (FFI) and decay rate (t). Levels of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), phospholamban (PLB) and PKB/Akt were assessed by Western blot. Ovx promoted body weight gain associated with significantly reduced serum E2 level and uterine weight, all of which were abolished by E2 replacement. Ovx depressed PS and ± dL/dt, prolonged TPS, TR90 and t, and enhanced resting FFI, all of which, with the exception of TPS, were restored by E2 replacement. Ovx did not significantly alter the levels of SERCA2a, PLB and total Akt, but did significantly reduce Akt activation (pAkt), pAkt/Akt ratio and SERCA2a/PLB ratio. These alterations in protein expression were again restored by E2 replacement. E2 enhanced PS and + dL/dt in vitro, which was abolished by the E2 receptor antagonist ICI182,780. In addition, Ovx reduced the myocyte responsiveness to increased extracellular Ca2+ and lessened increased stimulating frequency-induced decline in PS, both ablated by E2 replacement. These data suggest that both mechanical and protein functions of ventricular myocytes are directly regulated by the presence of the ovarian hormone estrogen.