| Estrogen has potential beneficial effects on cardiovascular diseases, as an example of preventing myocardial remodeling and heart failure. The incidence and severity of cardiovascular diseases in premenopausal women and postmenopausal women who take estrogen-replacement therapy are lower than in age-matched men.It has been reported that the activation of nuclear factor kappa B (NF-κB)is required for the development of myocardial remodeling and heart failure.Estrogen exerts anti-inflammatory immunoprotection by regulating the activation of NF-κB and decreasing the release of inflammatory factors.And estrogen could inhibit NF-κB DNA binding activity in myocardium via its receptor-αandβ.To date,whether estrogen could exert protective effects on ventricular remodeling by regulating NF-κB signaling has not been reported.In our experiments,we established the model of hemodynamic overload by stretching hearts via Langendorff system(hemodynamic overload acts as one initiating agent of myocardial hypertrophy and plays an important role in the development of myocardial hypertrophy and heart failure)and using the method of culturing cardiac fibroblasts(CFs), then we observed the effect of 17β-estradiol(E2)on cardiac dysfunction of isolated rat hearts exposed to mechanical stretching and on AngⅡ-induced cardiac fibroblasts proliferation and differentiation,and investigate whether estrogen ameliorate cardiac function and prevent CFs differentiation through the regulation of NF-κB signaling.We found that in stretching group,left ventricular developed pressure(LVDP),maximal positive values of the first derivative of pressure(+dP/dt),and maximal negative values of the first derivative of pressure(-dP/dt)were decreased by 42.7%,43.2%,and 43.5%, respectively,compared with untreated control group(P＜0.01),indicating that ventricular stretching depressed the cardiac function. Pre-administration of 100nM E2 could ameliorate the depressed cardiac function of rat hearts induced by acute ventricular stretching(LVDP, +dP/dt,and -dP/dt were increased by 36.1%,22.4%,and 20.6%, respectively,compared with untreated stretched hearts).In addition,the levels of tumor necrosis factor-alpha(TNF-alpha)in myocardium and coronary effluents were significantly increased following stretching compared to control group,and NF-kB binding activity which regulates TNF-alpha expression was also increased.Meanwhile,the upstream of NF-kB,the phosphoryation of p38 mitogen-activated protein kinase (MAPK)was increased.In E2 treated hearts,the levels of phospho-p38MAPK,NF-κB binding activity,and TNF-alpha in myocardium were significantly reduced by 56.9%,50%,and 35.7%, respectively,compared with untreated stretched hearts.The beneficial effects of E2 on the stretched hearts were partly abolished by ICI182,780, the specific antagonist of ER.In cell culture study,we found that AngⅡ(1μM)could stimulate the CFs proliferation and differentiation to myofibroblasts,with the increased level of phospho-p38MAPK and the activation of NF-κB. Pretreatment of E2 could inhibit AngⅡ-induced the proliferation of CFs, decrease AngⅡ-induced the expression of alpha-smooth muscle actin (α-SMA)(20%reduction compared with AngⅡgroup),preventing CFs differentiation to the myofibroblasts.In addition,E2 reduced phospho-p38 MAPK and NF-κB binding activity levels in CFs in response to AngⅡby 40%and 55%,suggesting that E2 may inhibit the CFs differention by mediating the activation of p38 MAPK/NF-κB signaling.Our results suggest that estrogen could improve stretching-induced cardiac dysfunction and interrupt AngⅡ-induced the proliferation of CFs and the differentiation of CFs to the myofibroblast phenotype. Furthermore,the mechanism may be related to the regulation of the activation of NF-κB signaling.
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