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

Abstract

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 (±d L/d t), 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 E₂and uterine weight, all of which were abolished by E₂. Ovx depressed PS and ±d L/d t, 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 +d L/d t 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.