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Am J Physiol Heart Circ Physiol 284: H1800-H1807, 2003. First published January 16, 2003; doi:10.1152/ajpheart.00866.2002
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Vol. 284, Issue 5, H1800-H1807, May 2003

Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation

Jun Ren1, Kadon K. Hintz2, Z. K. Fariba Roughead3, Jinhong Duan1, Peter B. Colligan2, Bonnie H. Ren1, Kap J. Lee4, and Huawei Zeng3

1 Division of Pharmaceutical Sciences, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071-3375; 2 University of North Dakota School of Medicine, Grand Forks 58203; 3 United States Department of Agriculture, Grand Forks Human Nutrition Research Center, Agricultural Research Service, Grand Forks 58202; and 4 Center for Biomedical Research, University of North Dakota School of Medicine, Grand Forks, North Dakota 58203

Women with functional ovaries have a lower cardiovascular risk than men and postmenopausal women. However, estrogen replacement therapy remains controversial. This study examined the effect of ovarian hormone deficiency and estrogen replacement on ventricular myocyte contractile function and PKB/Akt activation. Nulliparous female rats were subjected to bilateral ovariectomy (Ovx) or sham operation (sham). A subgroup of Ovx rats received estrogen (E2) replacement (40 µg · kg-1 · day-1) for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening (±dL/dt), fura 2 fluorescence intensity (FFI), and decay rate. Levels of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), phospholamban (PLB), and Akt were assessed by Western blot. Ovx promoted body weight gain associated with reduced serum E2 and uterine weight, all of which were abolished by E2. Ovx depressed PS and ±dL/dt, prolonged TPS, TR90, and decay rate, and enhanced resting FFI, all of which, with the exception of TPS, were restored by E2. Ovx did not alter the levels of SERCA2a, PLB, and total Akt, but significantly reduced Akt activation [phosphorylated Akt (pAkt)], pAkt/Akt, and the SERCA2a-to-PLB ratio. These alterations in protein expression were restored by E2. E2 enhanced PS and +dL/dt in vitro, which was abolished by the E2 receptor antagonist ICI-182780. Ovx reduced myocyte Ca2+ responsiveness and lessened stimulating frequency-induced decline in PS, both ablated by E2. These data suggest that mechanical and protein functions of ventricular myocytes are directly regulated by E2.

ovariectomy; cardiac myocyte; contraction, intracellular Ca2+


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