异甘草素对低氧诱导的大鼠肺动脉结构重建的影响

Effects of isoliquiritigenin on pulmonary vascular remodeling in chronic hypoxia rat model

目的观察异甘草素对缺氧性肺动脉高压(HPH)大鼠模型的肺动脉压力的变化,右心室肥厚程度及肺血管结构重建的影响,探讨异甘草素对HPH的抑制作用及其可能机制。方法雄性SD大鼠30只随机分为对照组、HPH组、异甘草素组,每组各10只。HPH组和异甘草素组大鼠置于缺氧箱中建立大鼠HPH模型。异甘草素组中,每只大鼠腹腔注射异甘草素剂量为10 mg/(kg·d),从缺氧前1周开始给药直到缺氧结束。对照组和HPH组大鼠腹腔注射等体积0.5%DMSO。测定各组大鼠平均右心室压力(RVSP);称重法测得各组大鼠右心室游离壁(RV)及左心室加室间隔(LV+S)质量,以及RV/(LV+S);HE染色观察肺动脉病理形态改变,计算血管厚度百分比(WT%)及面积百分比(WA%);ELISA法检测各组大鼠血清及肺组织中的超氧化物歧化酶(SOD)及丙二醛(MDA)的含量。Real-time PCR检测各组大鼠肺组织中的NADPH氧化酶4(NOX4)mRNA的表达。结果 HPH组大鼠RVSP、RV/LV+S、WT%,以及WA%明显高于对照组大鼠(P<0.01),然而异甘草素组大鼠RVSP、RV/LV+S、WT%,以及WA%均明显低于HPH组大鼠(P<0.01)。HPH组大鼠肺组织及血清中的SOD含量较对照组明显降低,而MDA含量则明显增高(P<0.01)。异甘草素组大鼠肺组织及血清中的SOD含量较HPH组大鼠明显增高,而MDA含量则明显降低(P<0.01)。Real-time PCR结果显示,异甘草素有效抑制了低氧诱导的大鼠肺组织中NOX4 mRNA的高表达(P<0.01)。结论异甘草素抑制由低氧诱导的HPH大鼠肺动脉压力升高、右心室肥厚,以及肺动脉管壁的增厚,可能与异甘草素抑制HPH大鼠体内的氧化损伤有关。

Objective To investigate the possible effect and the underlying mechanism of isoliquiritigenin（ ISL）on hypoxic pulmonary hypertension（ HPH） through observation of the changes of pulmonary artery pressure,vascular remodeling,and right ventricular hypertrophy in a chronic hypoxia rat model. Methods Thirty male Sprague-Dawley rats were randomly divided into 3 groups（ 10 rats per group） ： normoxia group,hypoxia group and hypoxia group treated with ISL. For hypoxia group treated with ISL,rats were injected intraperitoneally ISL [10 mg/（ kg·day）,dissolved in 0. 5%DMSO]. For normoxia and hypoxia groups,rats were injected intraperitoneally equal amount of 0. 5% DMSO. After 4 weeks hypoxia exposure,the right ventricle systolic pressure（ RVSP） was recorded using Power Lab Software. The weight ratio of [right ventricle（ RV）/left ventricle ＋ septum（ LV ＋ S） ] was calculated as an index of RV hypertrophy. After HE staining,the percent medial wall thickness（ WT%） and percent medial wall area（ WA%） in small pulmonary arteries were determined. The content of superoxide dismutase（ SOD） and malonaldehyde（ MDA） were measured using commercial kits. NADPH oxidase 4（ NOX4） mRNA levels in lung tissues were measured by Real-time PCR. Results The average RVSP,ratio of RV/LV ＋ S,WT%,and WA% of hypoxia group were increased significantly compared with the normoxia group（ P 0. 01）. However,the average RVSP,ratio of RV/LV ＋ S,WT%,and WA% of hypoxia treated with ISL group were much lower than those of hypoxia group（ P 0. 01）. In addition,the result showed that hypoxia decreasedthe level of SOD,companied with an increased level of MDA both in lung tissue and in serum（ P 0. 01）. ISL treatment elevated the level of SOD and reduced the level of MDA（ P 0. 01）. Real-time PCR result showed ISL obviously downregulated the NOX4 mRNA levels in lung tissues（ P 0. 01）. Conclusion ISL may have beneficial effects on the HPH and these effects may be related to the inhibition of the oxidative stress caused by hypoxia.