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

3Chemistry Department, Winston-Salem State University, Winston-Salem, NC
Menopause (New York, N.Y.) (Impact Factor: 2.81). 03/2013; DOI: 10.1097/GME.0b013e318280589a
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure (HF). While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science implicates activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue angiotensin II (Ang II) and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces reactive oxygen species (ROS) that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen insufficient or deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence that estrogen modulates tissue RAAS and NOS systems and related intracellular signaling pathways, in part via the membrane G protein-coupled estrogen receptor GPR30. Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD, and inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS systems, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic HF that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.
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