卡托普利对缺氧型肺动脉高压大鼠影响及机制

Impact and mechanism of Captopril on the pulmonary arterial hypertension model induced by chronic hypoxia in rats

目的 观察慢性缺氧所致肺动脉高压大鼠肺血流动力学、肺动脉病理和肺组织3-磷酸肌醇激酶/蛋白激酶B（PI3K/Akt） mRNA、蛋白表达变化,探讨卡托普利对慢性缺氧所致肺动脉血流动力学、肺动脉平滑肌增殖及PI3 K/Akt mRNA、蛋白表达的影响.方法 将30只雄性SD大鼠随机分为对照组（n=10）、肺高压组（n=10）、卡托普利组（n=10）.后两组慢性缺氧4周后,建立缺氧型肺动脉高压动物模型.卡托普利组大鼠每天灌胃卡托普利100 mg/（kg·d）,对照组和肺高压组每天灌胃等量生理盐水.慢性缺氧28 d后,测定平均肺动脉压（mPAP）及右室收缩压（sRVP）;观察右室肥厚程度,计算右室重量/（左室＋室间隔）重量比值,以[RV/（LV＋S）]表示;计算肺中、小血管肌型动脉相对中膜厚度（RMT）;采用逆转录-聚合酶链反应（RT-PCR）法、Western blot分别观察大鼠肺组织PI3K/Akt mRNA、蛋白表达.结果 与对照组比较,肺高压组大鼠mPAP为（38.3±2.3） mm Hg（1 mm Hg=0.133 kPa）、sRVP为（57.1 ±4.8）mm Hg、RV/（LV＋S）为（0.47±0.03）％、RMT为（53.9±5.9）％,比值显著增高（P＜0.05）,肺组织PI3 K/Akt mRNA为（6.2±0.4）、蛋白表达水平显著增高（P＜0.05）.与肺高压组比较,卡托普利组mPAP为（16.5±0.6）mmHg、sRVP为（22.8-±0.7）mm Hg、RV/（LV＋S）为（0.35±0.03）％、RMT为（30.5±3.8）％,比值显著低于肺高压组（P＜0.05）,肺血管PI3K/Akt mRNA表达水平显著降低（2.5±0.4,P＜0.05）;卡托普利组mPAP、sRVP、RV/（LV＋S）与对照组比较,差异均无统计学意义（P＞0.05）;PI3K/Akt mRNA和蛋白表达水平差异无统计学意义（P＞0.05）.结论 慢性缺氧导致大鼠产生肺动脉高压、肺动脉平滑肌增殖并且其肺组织PI3K/Akt mRNA、蛋白表达增加,而口服卡托普利降低慢性缺氧大鼠肺动脉高压、平滑肌增殖和下调肺组织PI3K/Akt mRNA、蛋白表达.

Objective To investigate the effects of Captopril on the hemodynamic changes,the proliferation of pulmonary arterial smooth muscle cells and phosphatidylinositol 3 kinase （PI3K）/protein kinase B （Akt） mRNA and protein expression in pulmonary arterial hypertension （PAH） induced by chronic hypoxia in rats.Methods Thirty male SD rats were randomly divided into control group （n =10）,PAH group （n =10） and Captopril group （n =10）.The rats in PAH group and Captopril group were treated with chronic hypoxia,and those in Captopril group were given intragastric administration of Captopril 100 mg/（kg·day）,while other groups were given the intragastric administration of the same volume of normal saline.The rats in each group were sacrificed at the end of experiment （28th day）.The hemedynamics of PAH was measured and the morphological parameters relevant to the proliferation of pulmonary arterial smooth muscle cells were observed.The reverse transcriptase-polymerase chain reaction （RT-PCR） and Western blotting were used to detect the expression levels of PI3K/Akt mRNA and protein in the pulmonary tissues.Results The PAH group had significantly higher mPAP [（38.3 ± 2.3） mm Hg （1 mm Hg =0.133 kPa）],sRVP [（57.1 ±4.8） mmHg],RV/（LV ＋S） ratio [（0.47±0.03）％],and RMT [（53.9-±5.9）％] than in control group （all P ＜0.05）.The levels of PI3K/Akt mRNA and protein expression were significantly up-regulated in PAH group as compared with control group （P ＜ 0.05）.The Captopril group had significantly lower mPAP [（16.5 ±0.6） mm Hg],sRVP [（22.8 ±0.7） mm Hg],RV/（LV ＋ S） ratio [（0.35 ± 0.03） ％],and RMT [（30.5 ± 3.8） ％] （all P ＜ 0.05） than in control group.The levels of PI3K/Akt mRNA and protein expression were significantly down-regulated in Captopril group as compared with control group （P ＜ 0.05）.There was no significant differences in mPAP,sRVP,RV/（LV ＋ S）,and the expression levels of PI3K/Akt mRNA and protein between control group and Captopril group （all P ＞ 0.05）.Conclusion Captopril inhibits the pathological progress of the PAH,which may be contributed to the inhibition of up-regulation of the PI3K/Akt in the rats with PAH induced by chronic hypoxia.