雷洛昔芬对慢性低氧大鼠肺动脉血管重构的作用

Effect of Raloxifene on Pulmonary Artery Remodeling in Chronic Hypoxic Rats

关键词:  雷洛昔芬  低氧  肺动脉重构  肺动脉平滑肌细胞

Key words:  raloxifene  hypoxia  pulmonary arterial remodeling  pulmonary arterial smooth muscle cell

摘要:

目的 探讨雷洛昔芬对慢性低氧大鼠肺动脉结构重构的调节作用。方法 选取体质量180~200 g的健康SD大鼠40只，♂，随机分为常氧组、低氧组、低氧+17β-雌二醇组、常氧+雷洛昔芬组、低氧+雷洛昔芬组；原代培养大鼠肺动脉平滑肌细胞(pulmonary arterial smooth muscle cells，PASMC)分组同上。采用间断常压低氧法建立慢性低氧大鼠和细胞模型，采用免疫组织化学法检测肺动脉平滑肌的增殖情况，以蛋白免疫印迹法检测PASMC小窝蛋白(Caveolin-1，Cav-1)的表达，采用荧光探针法检测PASMC活性氧(ROS)的含量。结果 与常氧组相比，低氧组大鼠肺小动脉平滑肌增殖、中膜厚度及肌化程度明显增加(P<0.01)，雷洛昔芬可显著抑制低氧诱导的肺动脉改变(P<0.05)。低氧组大鼠PASMC中ROS浓度增加(P<0.01)，给予低氧组大鼠雷洛昔芬治疗，可下调ROS浓度(P<0.05)。低氧组大鼠PASMC中Cav-1表达显著降低(P<0.01)，雷洛昔芬可改善其低表达(P<0.05)。雷洛昔芬的缓解肺动脉重构、上调Cav-1的表达、减少ROS的产生、抑制PASMC增殖的效果类似于17β-雌二醇。结论 雷洛昔芬可上调PASMC中Cav-1的表达，减少ROS的产生，抑制PASMC增殖，在缓解慢性低氧大鼠的肺动脉重构中发挥重要作用。

Abstract:

OBJECTIVE To explore effect of raloxifene on pulmonary artery remodeling in chronic hypoxic rats. METHODS Forty rats were divided 5 groups: normal oxygen group (n=8), hypoxia group (n=8), hypoxia+17β-estraiol group (75?mg·kg^-1·d^-1, n=8), normal oxygen+raloxifene group(10 mg·kg^-1·d^-1, n=8) and hypoxia+raloxifene group(10?mg·kg^-1·d^-1, n=8). Pulmonary artery smooth muscle cells (PASMC) were cultured from pulmonary artery in rats. The chronic hypoxic animal and cell models were established by regular exposing the rats to normabaric hypoxic conditions. The contents of proliferating cell and Caveolin-1(Cav-1) protein expressions were detected by immunohistochemical assay. Reactive oxygen species (ROS) was assessed by fluorescent probe assays. RESULTS Compared with rats in normal oxygen group, pulmonary proliferation, medial wall thickness and fully muscularized vessels were significantly enhanced in response to hypoxia (P<0.01). There were marked decreases in hypoxia groups with raloxifene treatment (P<0.05). The concentrations of ROS were significantly higher in hypoxia group than normal oxygen groups (P<0.01). Raloxifene inhibited the ROS concentrations (P<0.05). Cav-1 protein expressions were decreased in hypoxia groups (P<0.01) and were increased with raloxifene treatment (P<0.05). the efficacy of raloxifene to alleviate the pulmonary arterial remodeling was similar to 17β-estraiol. CONCLUSION Raloxifene up-regulates the expressions of Cav-1 protein, decreases ROS productions, and inhibits pulmonary artery PASMC proliferating. Raloxifene has important modulating effects on pulmonary vascular structural remodeling in chronic hypoxic rats.