雌激素及其代谢产物对去势低氧肺动脉高压大鼠烷烃单加氧酶和低氧诱导因子-1α表达的影响

Effect of Estradiol and its Metabolite on Hypoxic Induced Factor-1α and Alkane Hydroxylase in Experimental Rats With Ovariectomy and Hypoxic Pulmonary Hypertension

目的：探讨17β-雌二醇（E2）及2甲氧基雌二醇（2ME）对去势低氧肺动脉高压大鼠模型中烷烃单加氧酶（AIkB）和低氧诱导因子-1α（HIF-1α）的影响。方法：选6～7周龄雌性sD大鼠60只，去势手后采用随机数字表法将大鼠随机分为6组：常氧组（D=10），常氧＋E2组（n=1O），常氧＋2ME组（n=10），低氧组（n=10），低氧＋E2组（n=10），低氧＋2ME组（n=10）。低氧组持续低氧（24h，8周）；2ME组自造模之日起，每日皮下注射2ME（240μg／kg）；E2组每日皮下注射E2（20μg／kg）。连续饲养8周，以建讧低氧性肺动脉高压模型。测量平均肺动脉压（mPAP）后放血处死大鼠，观察有心室肥厚指数（RVHI），苏木素-伊红（HE）染色观察肺小动脉重构情况。采用免疫蛋白印迹法、反转录聚合酶链反应（RT-PCR）测定AIkB、HIF-1α的表达水平。结果：与常氧组比较，低氧组大鼠肺小动脉管壁增厚管腔变窄明显，mPAP、RVHI均显著升高，低氧＋E2组和低氧＋2ME组j：述形态学改变相对较轻，mPAP、RVHI均显著高于常氧组，且低氧＋E2组和低氧＋2ME组间无明显差异，常氧＋E2组和常氧＋2ME组肺小血管形态学无明显变化。HIF-1d表达水平在低氧组显著高于常氰组，低氧＋E2组、低氧＋2ME组亦升高，升高幅度不及低氧组，常氧＋E2组、常氧＋2ME组无明显变化。AlkB表达水平在低氧细显著低于常氧组，低氧＋E2组、低氧＋2ME组亦降低，降低幅度不及低氧组，常氧＋E2组、常氧＋2ME组无明显变化。结论：E2和2ME可能通过卜调低氧性肺动脉高压大鼠肺组织AlkB的表达，降低HIF-1α表达，进而缓解肺动脉高乐。

Objective： To explore the effects of 17β-estrogen （E2） and 2-methoxyestradiol （2ME） on hypoxic induced factor-1α （HIF-1α） and alkane hydroxylase （AlkB） in experimental rats with ovariectomy and hypoxic pulmonary hypertension. Methods： A total of 60 healthy female SD rats with castrated surgery were randomly divided into 6 groups： （1） Routine oxygen group, （2） Routine oxygen ＋ E2 group, the rats received subcutaneous injection orE2 （20 μg/kg·d）, （3） Routine oxygen ＋ 2ME group, the rats received 2ME （240 μg/kgod） and （4） Hypoxia group, （5） Hypoxia ＋ E2 group, （6） Hypoxia ＋ 2ME group, n=10 in each group and all animals were treated for 8 weeks to establish the hypoxic pulmonary hypertension model. The mean pulmonary artery pressure （mPAP） was measured after bloodletting, right ventricle hypertrophy index （RVHI） was calculated and small pulmonary arteryremodeling was observed by HE staining. The expression level of HIF-1α and AIkB were examined by RT-PCR and Western blot analysis. Results： Compared with Routine oxygen group, the rats in Hypoxia group had obviously thickened small pulmonary artery wall with narrowed lumen, increased rnPAP and RVHI; the above changes in Hypoxia ＋ E2 and Hypoxia ＋ 2ME groups were relatively smaller, their mPAP and RVHI were higher than Routine oxygen group, while mPAP and RVHI were similar between Hypoxia ＋ E2 and Hypoxia ＋ 2ME groups. There were no real morphological changes in small pulmonary vessels in Routine oxygen ＋ E2 and Routine oxygen ＋ 2ME groups. The HIF-1α expression was obviously elevated in Hypoxia group than Routine oxygen group, while the elevation was less in Hypoxia ＋ E2 and Hypoxia ＋ 2ME groups. HIF-1α expression had no real changes in Routine oxygen＋E2 and Routine oxygen ＋ 2ME groups. The AlkB expression was obviously reduced in Hypoxia group than Routine oxygen group, while the reduction was less in Hypoxia ＋ E2 and Hypoxia ＋ 2ME groups. AIkB expression had no real changes in Routine oxygen ＋ E2 and Routine oxygen ＋ 2ME groups. Conclusion： Estradiol E2 and 2ME could remit pulmonary hypertension which might be via up-regulating AlkB expression and down-regulating HIF- 1α expression in experimental rats with hypoxic pulmonary hypertension.