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

• Published in: American journal of physiology. Heart and circulatory physiology 2003-05, Vol.284 (5), p.H1800-H1807
• Main Authors: Ren, Jun, Hintz, Kadon K, Roughead, Z.K. Fariba, Duan, Jinhong, Colligan, Peter B, Ren, Bonnie H, Lee, Kap J, Zeng, Huawei
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; calcium; Calcium - pharmacokinetics; Calcium-Binding Proteins - metabolism; Calcium-Transporting ATPases - metabolism; cardiac output; cytochemistry; enzyme activity; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; estrogen replacement therapy; estrogens; Estrogens - pharmacology; Female; heart ventricle; intracellular calcium; Myocardial Contraction - drug effects; myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Ovariectomy; protein kinases; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - enzymology; Sarcoplasmic Reticulum Calcium-Transporting ATPases; ventricular myocyte contractile function; ventricular myocytes
• ISSN: 1522-1539; 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00866.2002

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 E2and 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.