罗格列酮通过激活PPARγ改善肺动脉高压大鼠肺动脉内皮依赖性舒张功能

摘要

AIM; To explore the effects of rosiglitazone, an agonist of peroxisome proliferator-aetivated receptor 7 ( PPARγ) , on pulmonary vascular endothelial function in the rat model of pulmonary hypertension. METHODS: Forty Sprague-Dawley (SD) rats were divided into 4 groups; normal control group, model group, rosiglitazone group and rosiglitazone plus GW9662 ( a specific blocker of PPARγ) group (10 rats in each group). The rat model of pulmonary hypertension was established by subcutaneous injection of monocrotaline at a dose of 60 mg/kg. The rats in normal control group were treated with subcutaneous injection of normal saline. Rosiglitazone (2.0 mg·kg-1·d-1) was given by intra-gastric administration once a day. GW9662 (0. 3 mg·kg-1·d-1 ) was also given by intragastric administration. Four weeks later, the blood was taken from the abdominal aorta for detecting the levels of endothelin ( ET-1) and nitric oxide ( NO) by ELISA. The pulmonary artery was isolated, and the vascular activities and the endothelial function were evaluated by wire myograph. Human pulmonary artery endothelial cells (HPAECs) were cultured in DMEM and treated with DMSO, rosiglitazone or rosiglitazone plus GW9662, then NO production in HPAECs was evaluated. RESULTS: Rosiglitazone administration improved the endothelium-dependent relaxation in pulmonary arteries. Rosiglitazone did not affect the endothe-lium-independent relaxation in pulmonary hypertensive rats. Rosiglitazone also decreased the plasma ET-1 level and increased the NO level in pulmonary hypertensive rats. PPAR-γ antagonist GW9662 blocked the effects of rosiglitazone mentioned above. Treatment with rosiglitazone significantly increased the NO production in cultured HPAECs, and this effect was also blocked by GW9662. CONCLUSION: Rosiglitazone improves pulmonary vascular endothelial function in the rat model of pulmonary hypertension by activation of PPAR-γ.%目的:探索过氧化物酶体增殖物激活受体γ(PPARγ)激动剂罗格列酮对肺动脉高压大鼠模型肺动脉血管内皮功能的影响.方法:(1)SD大鼠40只,分为正常对照组、模型组、罗格列酮组和罗格列酮+ GW9662(PPARγ拮抗剂)干预组,每组10只,以野百合碱(60 mg/kg)一次性皮下注射复制肺动脉高压大鼠模型,再灌胃给予罗格列酮(2.0 mg·kg-1·d-1)或罗格列酮+GW 9662 (0.3 mg·kg-1·d-1)干预.4周后,取血浆测一氧化氮(NO)及内皮素-1(ET-1)的水平,分离肺动脉二级分支,以微血管张力测定仪测定肺动脉血管功能变化情况.(2)体外培养人肺动脉内皮细胞株(HPAECs),探讨罗格列酮对HPAECs NO生成的影响.结果:罗格列酮可显著改善肺动脉高压大鼠血管内皮依赖性舒张功能,但不能显著改善非内皮依赖性舒张功能；罗格列酮干预可降低血浆ET-1水平,升高NO水平；但罗格列酮的以上作用在同时给予PPARγ拮抗剂GW9662时显著被减弱.体外实验证实,罗格列酮可显著增加HPAECs的NO生成,但该作用同样可被GW9662所阻断.结论:罗格列酮通过激活PPARγ改善肺动脉高压大鼠的血管内皮依赖性舒张功能可能是其治疗肺动脉高压的基础.