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Estrogen therapy, independent of timing, improves cardiac structure and function in oophorectomized mRen2.Lewis rats

Jessup, Jewell A. PhD; Wang, Hao MD, PhD; MacNamara, Lindsay M. BS; Presley, Tennille D. PhD; Kim-Shapiro, Daniel B. PhD; Zhang, Lili MD; Chen, Alex F. MD, PhD; Groban, Leanne MD

doi: 10.1097/GME.0b013e318280589a
Original Articles

Objective mRen2.Lewis rats exhibit exacerbated increases in blood pressure, left ventricular (LV) remodeling, and diastolic impairment after the loss of estrogens. In this same model, depletion of estrogens has marked effects on the cardiac biopterin profile concomitant with suppressed nitric oxide release. With respect to the establishment of overt systolic hypertension after oophorectomy (OVX), we assessed the effects of timing long-term 17β-estradiol (E2) therapy on myocardial function, myocardial structure, and the cardiac nitric oxide system.

Methods OVX (n = 24) or sham operation (Sham; n = 13) was performed in 4-week-old female mRen2.Lewis rats. After randomization, OVX rats received E2 immediately (OVX + E2-early; n = 7), E2 at 11 weeks of age (OVX + E2-late; n = 8), or no E2 at all (OVX; n = 9).

Results E2-early was associated with lower body weight, less hypertension-related cardiac remodeling, and decreased LV filling pressure compared with OVX rats without E2 supplementation. E2-late similarly attenuated the adverse effects of ovarian hormone loss on tissue Doppler–derived LV filling pressures and perivascular fibrosis, and significantly improved myocardial relaxation or mitral annular velocity (e′). Early and late exposures to E2 decreased dihydrobiopterin, but only E2-late yielded significant increases in cardiac nitrite concentrations.

Conclusions Although there are some similarities between E2-early and E2-late treatments in relation to preservation of diastolic function and cardiac structure after OVX, the lusitropic potential of E2 is most consistent with late supplementation. The cardioprotective effects of E2-late are independent of blood pressure and may have occurred through regulation of cardiac biopterins and nitric oxide production.

Supplemental digital content is available in the text.

From the Departments of 1Physiology and Pharmacology and 2Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC; 3Chemistry Department, Winston-Salem State University, Winston-Salem, NC; 4Translational Science Center and 5Department of Physics, Wake Forest University, Winston-Salem, NC; 6Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA; 7Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA; and 8Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, NC.

Received August 22, 2012; revised and accepted November 28, 2012.

J.A.J. and H.W. contributed equally to this project.

Funding/support: This work was supported, in part, by grants from the National Institutes of Health (R01-AG033727 to L.G., HL058091 to D.B.K.-S., and R01 GM077352 to A.F.C.) and the American Heart Association Grant-in-Aid (0855601GH to A.F.C.).

Financial disclosure/conflicts of interest: None reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (

Address correspondence to: Leanne Groban, MD, Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. E-mail:

© 2013 by The North American Menopause Society.