地高辛通过上调RGS2表达以减缓AngⅡ诱导小鼠高血压性心肌肥厚发生发展的研究

Digoxin Alleviates AngⅡ-induced Cardiac Hypertrophy by Increasing the Expression of RGS2

目的通过观察地高辛(Digoxin)干预血管紧张素Ⅱ(AngⅡ)诱导的ApoE-/-小鼠高血压性心肌肥厚模型后,对G蛋白调节因子2(regulator of G protein signaling 2,RGS2)的影响,探讨地高辛治疗高血压性心肌肥厚的作用与可能的机制。方法 30只雄性ApoE-/-小鼠随机分为对照组、AngⅡ模型组和AngⅡ+Digoxin治疗组。所有小鼠从术前1d至术后处死前均接受0.5%二甲基亚砜或地高辛溶液腹腔注射治疗,并且在术后28d获取心脏组织,通过组织学检查、苏木精-伊红(HE)染色切片分析技术评定心肌组织形态学变化、RGS2的mRNA及蛋白表达水平来评价地高辛的作用。结果与AngⅡ模型组相比,AngⅡ+Digoxin组全心重量、左心室壁厚度、心肌细胞直径均明显减少(P<0.05或P<0.01),RGS2mRNA变化不明显,而蛋白表达增高(P<0.01),心肌肥厚明显减轻。同时检测小鼠在术前3d,手术当天,术后3、7、14、28d的血压,发现AngⅡ+Digoxin组与AngⅡ模型组比较,术后7d和14d血压下降(均P<0.05),术后28d则差异无统计学意义。结论地高辛可能通过上调ApoE-/-小鼠高血压心肌肥厚模型RGS2的表达,有效减轻心肌肥厚,这说明地高辛可能在抑制心肌细胞肥大中起重要作用。

Objective To examine the effect of digoxin on the expression of regulator of G protein signaling 2（RGS2）in apolipoprotein E‐deficient（ApoE^‐/‐）mice with angiotensin Ⅱ‐induced cardiac hypertrophy and further explore the possible mechanism by which digoxin treats hypertensive cardiac hypertrophy.Methods Thirty male ApoE^‐/‐ mice were randomly divid‐ed into the following 3 groups：Control group ,AngⅡ model group ,AngⅡ ＋Digoxin treatment group. All mice were intraperito‐neally treated with 0.5% DMSO or digoxin from the day before operation to the day before sacrifice. Twenty‐eight days after the operation ,heart samples were harvested. The morphological changes of the cardiac tissues were evaluated by histopathologi‐cal examination and HE staining ,respectively. The protein and mRNA levels of RGS2 were determined to reflect the efficacy of digoxin.Results The whole heart weight ,the thickness of the left ventricular posterior wall ,and the myocyte diameter were significantly decreased in the AngⅡ ＋Digoxin treatment group as compared with those in the Ang Ⅱ model group（P〈0.05 for the thickness of the left ventricular posterior wall ;P〈0.01 for the whole heart weight and the myocyte diameter ）. The protein level of RGS2 was significantly increased in the Ang Ⅱ ＋Digoxin treatment group as compared with that in the Ang Ⅱ model group（P〈0.01） ,although the RGS2 mRNA level wasn’t significantly differ between the groups.Cardiac hypertrophy was pro‐foundly improved in the AngⅡ ＋Digoxin treatment group. Furthermore ,by monitoring the blood pressure at 3 days before oper‐ation ,on the day of operation ,and at 3 ,7 ,14 ,28 days after operation ,we found that digoxin delayed the increase of blood pres‐sure at day 7 and day 14 after operation but not at day 28.Conclusion Digoxin could effectively attenuate cardiac hypertrophy in ApoE^‐/‐ mice by upregulating the RGS2 expression ,suggesting the important role of digoxin in the suppression of cardiac hy‐pertrophy.