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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。
Objective To investigate the regulatory effect of raloxifene on structural remodeling of pulmonary artery in rats with chronic hypoxia. Methods Forty healthy SD rats weighing 180 ~ 200 g were randomly divided into normoxia group, hypoxia group, hypoxia + 17β-estradiol group, normoxia + raloxifene group, hypoxia group + Raloxifene group; primary cultured rat pulmonary arterial smooth muscle cells (PASMC) were grouped as above. Chronic hypoxic rat and cell models were established by intermittent normobaric hypoxia. The proliferation of pulmonary artery smooth muscle was detected by immunohistochemical method. The expression of caveolin-1 (Cav-1) in PASMC was detected by Western blotting , Using fluorescent probe detection of reactive oxygen species (PASMC) content. Results Compared with normoxia group, the proliferation, the thickness and the degree of muscle formation of pulmonary arterioles in hypoxia group were significantly increased (P <0.01), and raloxifene significantly inhibited hypoxia - induced changes in pulmonary artery (P < 0.05). The concentration of ROS in PASMC of hypoxia group was increased (P <0.01), while raloxifene treatment of hypoxia group could decrease ROS concentration (P <0.05). The expression of Cav-1 in PASMC of hypoxia group was significantly decreased (P <0.01), and raloxifene could improve its low expression (P <0.05). Raloxifene can relieve pulmonary artery remodeling, up-regulate the expression of Cav-1, decrease the production of ROS, and inhibit the proliferation of PASMC in a similar manner to 17β-estradiol. Conclusion Raloxifene can upregulate the expression of Cav-1 in PASMC, decrease the production of ROS, inhibit the proliferation of PASMC and play an important role in the mitochondrial remodeling in chronic hypoxia rats.