野百合碱诱导的大鼠肺动脉高压对大鼠肺Hippo信号通路相关分子表达的影响

目的:研究野百合碱诱导大鼠肺动脉高压时肺Hippo信号通路相关分子表达的变化,探讨Hippo信号通路对肺动脉高压发生发展的意义。方法:45只SD大鼠随机分为对照组(n=15)和模型组(n=30),模型组一次性给予颈部皮下注射野百合碱(60 mg/kg)建立肺动脉高压模型,对照组注射相同剂量的生理盐水。4周后通过右心导管术检测右心室收缩压(right ventricular systolic pressure,RVSP),计算右心室肥厚指数(right ventricular hypertrophy index,RVHI)和右心室质量指数(right ventricular mass index,RVMI);HE染色观察肺小动脉重构,计算中膜厚度百分比(medialthickness/external diameter, M/E%);Masson染色检测肺组织纤维化;免疫组化检测肺小动脉中Yes相关蛋白(Yes-associated protein,YAP)、tafazzin(TAZ)和TEAD蛋白表达的变化;Western blot和RT-qPCR检测肺组织中YAP、TAZ和TEAD蛋白和mRNA表达的变化。结果:与对照组相比,模型组大鼠的血管壁显著增厚,M/E%明显增高(P<0.01),肺组织纤维化明显;模型组的RVSP、RVHI和RVMI均明显高于对照组(P<0.01);免疫组化染色结果提示模型组肺小动脉YAP、TAZ和TEAD的蛋白水平显著高于对照组,Western blot和RT-qPCR结果显示肺组织YAP、TAZ和TEAD的蛋白和mRNA水平同样高于对照组(P<0.05)。结论:Hippo信号分子的激活可能促进了肺小动脉的重构,进而介导了野百合碱诱导的大鼠肺动脉高压的发生发展。

Effects of monocrotaline-induced pulmonary hypertension on expression of Hippo signaling pathway-related molecules in rat lung

AIM: To investigate the expression of Hippo signaling pathway-related molecules in the lung tissues of the rats with pulmonary hypertension induced by monocrotaline for exploring the significance of Hippo signaling pathway in the development of pulmonary hypertension. METHODS: SD rats(n=45) were randomly divided into control group(n=15) and model group(n=30). The rats in model group was given neck subcutaneous injection of monocrota-line at 60 mg/kg to establish pulmonary hypertension model, and the rats in control group was injected with the same volume of normal saline. Four weeks later, right ventricular systolic pressure(RVSP) was measured by right cardiac catheterization, and right ventricular hypertrophy index(RVHI) and right ventricular mass index(RVMI) were calculated. The remodeling of the pulmonary arterioles was observed by HE staining, and medial thickness/external diameter(M/E%) was evaluated. The fibrosis of lung tissues was detected by Masson staining. The protein expression of Yes-associated protein(YAP), tafazzin(TAZ) and TEAD was detected by immunohistochemistry, and the protein and mRNA levels of YAP, TAZ and TEAD in lung tissues were determined by Western blot and RT-qPCR. RESULTS: Compared with control group, the vascular wall in model group was thickened significantly, the M/E% was increased(P<0.01), the pulmonary fibrosis was obvious, and the RVSP and RVHI in model group were significantly higher than those in control group(P<0.01). The immunohistochemical staining showed that the protein expression of YAP, TAZ and TEAD in the pulmonary arterioles in model group was significantly higher than that in control group. The YAP, TAZ and TEAD protein and mRNA levels in the lung tissues were also higher than those in control group(P<0.05). CONCLUSION: The activation of Hippo signaling molecules may promote the remodeling of pulmonary arterioles and further regulate the development of monocrotaline-induced pulmonary hypertension.