Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation.
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 (E(2)) replacement (40 microg. kg(-1). day(-1)) for 8 weeks. Mechanical and intracellular Ca(2+) properties were evaluated including peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), fura 2 fluorescence intensity (FFI), and decay rate. Levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), and Akt were assessed by Western blot. Ovx promoted body weight gain associated with reduced serum E(2) and uterine weight, all of which were abolished by E(2). Ovx depressed PS and +/-dL/dt, prolonged TPS, TR(90), and decay rate, and enhanced resting FFI, all of which, with the exception of TPS, were restored by E(2). 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 E(2). E(2) enhanced PS and +dL/dt in vitro, which was abolished by the E(2) receptor antagonist ICI-182780. Ovx reduced myocyte Ca(2+) responsiveness and lessened stimulating frequency-induced decline in PS, both ablated by E(2). These data suggest that mechanical and protein functions of ventricular myocytes are directly regulated by E(2).
Ren
Jun
J
Division of Pharmaceutical Sciences, University of Wyoming College of Health Sciences, Laramie, WY 82071-3375, USA. jren@uwyo.edu
Hintz
Kadon K
KK
Roughead
Z K Fariba
ZK
Duan
Jinhong
J
Colligan
Peter B
PB
Ren
Bonnie H
BH
Lee
Kap J
KJ
Zeng
Huawei
H
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010052:Ovariectomy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D000077267:Fulvestrant; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C494920:Akt1 protein, rat