【摘要】 背景:绝经后冠心病妇女血清雌二醇降低与心功能减退、心室重构加重有关,绝经对慢性心力衰竭病情的影响及机制尚不十分清楚。沉默信息调节因子1在心血管系统中发挥保护作用。目的:研究沉默信息调节因子1在卵巢切除加重小鼠慢性心力衰竭中的作用及机制。方法:选择野生型雌性C57BL/6J小鼠及沉默信息调节因子1基因敲除的雌性C57BL/6J小鼠进行实验。(1)将野生型小鼠随机分为:假手术组、主动脉缩窄组、卵巢切除+主动脉缩窄组、卵巢切除+主动脉缩窄+雌二醇组。术后第1天开始,卵巢切除+主动脉缩窄+雌二醇组大鼠按照0.2 mg/(kg·d)的剂量给予苯甲酸雌二醇皮下注射,其余各组大鼠给予等剂量生理盐水皮下注射,共8周。(2)将沉默信息调节因子1基因敲除小鼠随机分为:沉默信息调节因子1基因敲除+假手术组、沉默信息调节因子1基因敲除+主动脉缩窄组。(3)实验分为5组:阴性对照腺病毒组、阴性对照腺病毒+主动脉缩窄组、过表达沉默信息调节因子1腺病毒+主动脉缩窄组、阴性对照腺病毒+卵巢切除+主动脉缩窄组、过表达沉默信息调节因子1腺病毒+卵巢切除+主动脉缩窄组。通过多点注射阴性对照腺病毒或过表达沉默信息调节因子1的腺病毒实现沉默信息调节因子1的过表达。(4)造模后8周,检测左心室收缩末内径、左心室舒张末内径、左心室射血分数、血清雌二醇、脑钠肽水平、子宫质量、心肌病理改变及沉默信息调节因子1表达水平。结果与结论:(1)与假手术组比较,主动脉缩窄组小鼠左心室收缩末内径、左心室舒张末内径、血清脑钠肽水平显著增加,左心室射血分数、心肌沉默信息调节因子1表达水平显著降低(P <0.05);与主动脉缩窄组比较,卵巢切除+主动脉缩窄组小鼠左心室收缩末内径、左心室舒张末内径、血清脑钠肽水平显著增加,左心室射血分数、血清雌二醇水平、心肌沉默信息调节因子1表达水平显著降低(P <0.05);沉默信息调节因子1基因敲除+主动脉缩窄组小鼠不表达沉默信息调节因子1,左心室收缩末内径、左心室舒张末内径、血清脑钠肽水平显著增加,左心室射血分数显著降低(P <0.05);与阴性对照腺病毒+卵巢切除+主动脉缩窄组比较,过表达沉默信息调节因子1腺病毒+卵巢切除+主动脉缩窄组小鼠左心室收缩末内径、左心室舒张末内径、血清脑钠肽水平显著降低,左心室射血分数、心肌沉默信息调节因子1表达水平显著增加(P <0.05);(2)结果说明,卵巢切除起到加重小鼠慢性心力衰竭病情的作用,抑制心肌中沉默信息调节因子1表达是与该作用相关的分子机制。更多还原

【Abstract】 BACKGROUND:Decreased serum estradiol in postmenopausal women with coronary heart disease is related to decreased heart function and ventricular remodeling aggravation.The effect of menopause on chronic heart failure and its mechanism are still unclear.Silent information regulator 1 plays a protective role in the cardiovascular system.OBJECTIVE:To investigate the effect of silent information regulator 1 on aggravating chronic heart failure in ovariectomized mice and its mechanism.METHODS:Experiment 1:Wild-type female C57 BL/6 J mice and female C57 BL/6 J mice with knockout of silent information regulator 1 were selected.The wild-type mice were randomly divided into four groups:a sham surgery grou p,an aortic stenosis group,an ovariectomy+aortic stenosis group,and an ovariectomy+aortic stenosis+estradiol group.From the first day after surgery,mice in the ovariectomy+aortic stenosis+estradiol group were given subcutaneous injection of estradiol benzoate at a dose of 0.2 mg/kg per day,and mice in the other groups were injected subcutaneously with the same dose of normal saline for 8 weeks.Experimental2:Mice with knockout of silent information regulator 1 were randomly divided into a silent information regulator 1 knockout+sham surgery group and a silent information regulator 1 knockout+aortic stenosis group.Experimental 3:There were five experimental groups:a negative control adenovirus group,a negative control adenovirus+aortic stenosis group,an overexpression of silent information regulator 1 adenovirus+aortic stenosis group,a negative control+adenovirus ovariectomy+aortic stenosis group,and an adenovirus overexpressing silent information regulator 1+ovariectomy+aortic stenosis group.Overexpression of silent information regulator 1 was achieved by multi-point injection of negative control adenovirus or adenovirus overexpressing silent information regulator 1.Eight weeks after modeling,we detected the left ventricular end-systolic diameter,left ventricular end-diastolic diamete r,left ventricular ejection fraction,serum estradiol level,brain natriuretic peptide level,uterine mass,myocardial pathological changes,and the expression level of silent information regulator 1.RESULTS AND CONCLUSION:Compared with the sham surgery group,the left ventricular end-systolic diameter,left ventricular end-diastolic diameter,and serum brain natriuretic peptide level were significantly increased,and the left ventricular ejection fraction and the expression level of myocardial silent information regulator 1 were significantly decreased in the aortic stenosis group(P <0.05).Compared with the aortic coarctation group,the left ventricular endsystolic diameter,left ventricular end-diastolic diameter,and seru m brain natriuretic peptide level were significantly increased,and the left ventricu lar ejection fraction,serum estradiol level,and the expression level of myocardial silent information regulator 1 were significantly reduced in the ovariectomized+a o rtdc stenosis group(P <0.05).Compared with the aortic coarctation group,silent information regulator 1 was not expressed in the silent information regulator1 knockout+aortic stenosis group,in which the left ventricular end-systolic diameter,left ventricular end-diastolic diameter,and serum brain natriuretic peptide level were significantly increased,and the left ventricular ejection fraction was significantly decreased(P <0.05).Compared with the negative control adenovirus+ovariectomy+aortic stenosis group,the left ventricular end-systolic diamete r,left ventricular end-diastolic diameter,and serum brain natriuretic peptide level were significantly reduced,and the left ventricular ejection fraction and the expression level of myocardial silent information regulator 1 were significantly increased in the adenovirus overexpressing silent information regulator l+ovariectomy+aortic stenosis group(P <0.05).These results indicate that ovariectomy can aggravate chronic heart failure in mice,and the molecular mechanism is to inhibit the expression of silent information regulator 1 in myocardium.更多还原