| Backgroud: Cardiovascular diseases are one of the leading causes of death all over the world and display significant gender-based differences. Premenopausal women have reduced risk compared with men, the incidence of cardiovascular disease increases significantly after menopause. Because ovarian activity decreases in the postmenopausal period, it is believed that reduced estrogen levels contribute to development of hypertension and to the increase of prevalence in cardiovascular disease in postmenopausal women. Estrogen replacement therapy (ERT) has been used to treat postmenopausal symptoms and to reduce the risk of cardiovascular disease. However, recent large clinical trials failed to demonstrate cardiovascular beneficial effects of ERT and have even suggested increased cardiovascular risk during the initial treatment period.Estrogen has nongenomic and genomic actions on many target tissues. These effects are mediated through at least two estrogen receptors (ERs) called estrogen receptor a and estrogen receptor |3 that may exist as nuclear or membrane-bound receptors. The nuclear receptors resulted in estrogen-estrogen receptor complexes serve as transcription factors that alter gene expression,called genomic actions; The membrane-bound receptors regulate some transcription factor by cross-talking with the intracellular signal pathway, called nongenomic actions. In the cardiovascular system, ERs are expressed in endothelial, smooth muscle, and myocardial cells. Recently, it was reported that the expression and distribution of ERs were mediated by estrogen. But it is not clear that the expression of ERs in left ventricle of ovariectomized female rats.The effects of estrogen on vascular tone and inhibition of vascular smooth muscle cell growth have been attributed in part to modulation of the renin-angiotensin system(RAS). In vascular smooth muscle cells, estrogen causes downregulation of angiotensin type 1 receptor(AT1R) and decreases AT1R-mediated signaling of angiotensin II. Angiotensin-converting enzyme (ACE) inhibitor-enalapril and angiotensin receptor II inhibitor-irbesartan, inhibit the formation of angiotensin II (Ang II) and the binding of Ang II to AT1R, reducing the biological effect of Ang II. Additionally, there is no report about whether ERs expression are modulated by RAS inhibitors.Objective: (1)We try to explore the effect of estrogen deficient on the expression of ERs in left ventricle of ovariectomized female rats.(2) To investigated the effect of RAS inhibitors on hypertrophy in ovariectomized female rats, the relation of the efffect with the expression of ERs. Estrogen deficient is an important motivation of myocardial hypertrophy, this study will illuminate the effects of ERs on hypertrophy induced by AAC in ovariectomized female rats, the mechanism for the contradictory effects of estrogen replacement therapy(ERT) on cardiovascular desease, and the relationship between modulating ERs and cardiovascular protective effects of RAS inhibitors.Method:(1)We used ovariectomy (OVX) to induce a low level of estrogen after menopause in adult female (180±10g) Sprague-Dawley rats. Rats were OVX-sham operated as control.(2) One week after OVX, we applied abdominal aortic constriction (AAC) to produce a pressure overloaded cardiac hypertrophy. Both OVX-sham and AAC-sham operated rats were set as Control 1, OVX-sham operated with AAC rats were set as Control 2.(3) Three days after AAC, the ovariectomied rats were divided into four groups [OVX + AAC+ estrogen, OVX + AAC+ irbesartan, OVX + AAC+ enalapril and OVX + AAC+ normal sodium(myocardial hypertrophy)]. Rats of control 1 and control 2 were given NS simultaneously.(4) After 4 weeks of aortic banding, hemodynamics was evaluated by Power-Lab electrophysiolograph, blood was collected from carotid artery for estrogen level determination. (5)The hearts were harvested, the ratio of heart weight / body weight, the ratio of left ventricle weight / heart weight were calculated for the judgement of myocardial hypertrophy.(6)The expression of ERs and angiotensin II receptors in the left ventricle were evaluated with RT-PCR and Western-Blot.Result:(1) Compared with control, plasma estrogen level was significantly lower in ovariectomized rats without ERT, suggested the estrogen deficient model successfully established.(2) Compared with the intact rats with or without AAC, ovariectomy aggravated cardiac dysfunction and ventricular mass, suggesting that pressure overloading model successfully established. (1)Estrogen deficiency aggravated ventricular mass and cardiac dysfunction; (2)endogenous estrogen prevents the myocardial hypertrophy induced by pressure overloading;(3)exogenous estrogen could not prevent myocardium hypertrophy induced by OVX with AAC; (4)Myocardium hypertrophy induced by OVX with AAC was prevented by enalapril and irbesartan treatment.(3) Compared with the control, cardiac diastolic function was decreased significantly in OVX with AAC rats. These changes were restored by exogenous estrogen, enalapril and irbesartan treatment.(4) The expression of both mRNA and protein levels of AT1R were markedly increased in myocardium after OVX with AAC. Exogenous estrogen treatment did not reduce the AT1R expression.(5) Compared with the control, the expression of both ERαand ERβwere significantly downregulated after OVX with AAC. Estrogen, enalapril and irbesartan treatment aggravated the downregulation of ERαand upregulation of ERβexpression significantly.Conclusion:(1) Ovariectomy enhanced cardiac hypertrophy induced by pressure overloading. Endogenous estrogen could prevent cardiac hypertrophy and protect cardiovascular system;(2) the expression of ERs in myocardium changed in ovariectomied AAC rats, so that endogenous estrogen could not be fully replaced by exogenous estrogen for cardiovascular protective effect;(3) in addition to RAS inhibition, ERs expression modulation in cardiac tissues may contribute to the effects of enalapril and irbesartan on attenuating cardiac hypertrophy in menopause females. |
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