全反式维甲酸对高血压大鼠体内ACE2表达与一氧化氮信号的影响

Effects of all-trans retinoic acid on ACE2 gene expression and nitric oxide signaling in spontaneously hypertensive rats

目的:探讨全反式维甲酸(atRA)对高血压大鼠体内血管紧张素转换酶2(ACE 2)基因表达及一氧化氮(NO)信号的影响。方法:采用自发性高血压大鼠(SHR)及其同源对照W KY大鼠,经腹腔注射atRA,为期1月。分别用实时荧光定量PCR,N orthern印迹及免疫印迹技术测定atRA治疗后SHR体内ACE 2、血管紧张素Ⅱ1型受体(AT1)的表达情况,以硝酸还原酶法检测血清NO水平。结果:与W KY对照组相比,SHR心脏ACE 2的mRNA和蛋白表达下调[mRNA拷贝数比值:(0.06±0.02)vs.1;蛋白吸光度比值:(0.73±0.05)vs.1,P均<0.01],atRA(低、高剂量atRA组)治疗后SHR心脏ACE 2表达上调[mRNA:(0.23±0.08),(0.53±0.18)vs.(0.06±0.02);蛋白水平上升:(0.9±0.07),(0.92±0.08)vs.(0.73±0.05),P均<0.05],同时出现AT1表达降低、血清NO水平增高以及血压下降(P均<0.05)。结论:长期atRA治疗促进SHR大鼠心脏ACE 2的表达增加,导致体内NO增加,血压下降,提示转录调节剂atRA很可能对人类高血压病防治具有一定的价值。

Objective： The aim of the present study is to explore effects of all-trans retinoic acid （atRA） on ACE2 expression and NO signaling in hypertension. Methods： Twelve-week-old male spontaneously hypertensive rats （SHR） were treated with atRA given as daily intraperitoneal injection for one month; age-and sex-matched Wistarkyoto （WKY） rats and placebo-treated SHR served as controls. Real-time PCR. Northern blot, and Western blot were performed to examine expressions of ACE2 and AT1receptor in rats before and after atRA treatment. Serum NO levels were determined with nitrate reductase. Results ： In placebo-treated SHR, ACE2 mRNA and protein expression were markedly depressed compared with WKY rats [mRNA copy ratio： （0. 06±0. 02） vs. 1 ; protein absorbance ratio. （0, 73±0. 05） vs. 1, P〈0. 01, respectively]. However, in atRA-treated SHR, a significant up-regulation of ACE2 expression was observed in heart [mRNA ： （0. 23±0. 08）, （0. 53±0. 18） vs. （0. 06±0. 02） ; protein level ascensused： （0. 9±0.07）. （0.92±0. 08） vs. （0.73±0.05）, P〈0.05, all], accompanied by a reduction of AT1expression, an elevation of serum nitric oxide and a decrease of blood pressure （P〈0. 05, all）. Conclusion： Increased ACE2 expression by atRA contributes to a shift of Ang Ⅱ /NO balance and a decrease of blood pressure in SHR. Thus. atRA, as a transcription-modulating drug may have potentially clinical value in the prevention and treatment of human essential hypertension.