依帕司他对肺动脉高压大鼠肺血管重构的影响

Effect of Epalrestat on Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension Rats

关键词:  依帕司他  肺动脉高压  肺血管重构  转化生长因子-β1  醛糖还原酶

Key words:  epalrestat  pulmonary arterial hypertension (PAH)  pulmonary vascular remodeling  TGF-β1  aldose reductase

摘要:

目的 通过观察依帕司他（epalrestat，EPS）对野百合碱（monocrotaline，MCT）诱导的肺动脉高压（pulmonary arterial hypertension，PAH）大鼠肺血管重构的保护作用，探讨其作用是否与其抑制转化生长因子-β1（TGF-β1）和醛糖还原酶（aldose reductase，AR）的表达有关。方法 SD大鼠48只，随机分为正常对照组、MCT组、EPS 50 mg·kg^-1组及EPS 100 mg·kg^-1组，每组12只。MCT（60 mg·kg^-1）皮下注射诱导PAH大鼠模型。连续灌胃给药4周后，由右颈外静脉将直径为0.5 mm的Cournand心导管缓慢推进到右心室和肺动脉，用MedLab多导生理记录仪分别记录右心室收缩压（right ventricular systolic pressure，RVSP）和平均肺动脉压（mean pulmonary arterial pressure，mPAP）。HE染色观察肺动脉病理学变化，Masson染色观察肺动脉胶原沉积的变化。免疫组化法检测肺动脉AR的蛋白表达。qPCR和（或）Western blot检测肺动脉增殖细胞核抗原（PCNA）、I型胶原蛋白（collagen I）、AR和TGF-β1的表达。结果 EPS连续给药4周后能明显降低PAH大鼠RVSP及mPAP，减轻肺血管重构，降低肺动脉PCNA、collagen I表达。同时，EPS还能明显抑制肺动脉AR和TGF-β1的表达。结论 EPS对MCT诱导的PAH大鼠肺血管重构具有一定的抑制作用，其机制可能与抑制TGF-β1介导AR的表达有关。

Abstract:

OBJECTIVE To investigate the protective effect of epalrestat on pulmonary vascular remodeling in rats with monocrotaline(MCT)-induced pulmonary arterial hypertension(PAH), and explore whether the effect was related to inhibiting the expression of TGF-β1 and aldose reductase(AR). METHODS Forty-eight rats were randomly divided into four groups, with 12 rats per group, as follows:control group, MCT group, epalrestat 50 mg·kg^-1 group and epalrestat 100 mg·kg^-1 group. PAH model was established by subcutaneous injection of MCT at the dose of 60 mg·kg^-1. After 4 weeks of continuous gavage, the Cournand catheter with a diameter of 0.5 mm was slowly pushed to the ventricle and pulmonary artery from the right external jugular vein. At the end of experiment, the right ventricular systolic pressure(RVSP) and mean pulmonary artery pressure(mPAP) were monitored by MedLab system. Pathological changes and collagen deposition of pulmonary artery was observed by HE staining and Masson respectively. The aldose reductase(AR) expression in pulmonary artery was measured by immunohistochemistry. The expression of proliferating cell nuclear antigen(PCNA), collagen I, TGF-β1 and AR were analyzed by qPCR and Western blot. RESULTS Epalrestat treatment for 4 weeks attenuated RVSP, mPAP and pulmonary vascular remodeling of PAH rats. Furthermore, pulmonary arteries collagen accumulation and PCNA and collagen I expression were both significantly suppressed by epalrestat treatment. The expression of TGF-β1 and AR were obviously decreased in pulmonary arteries from PAH rats with epalrestat treatment. CONCLUSION These findings demonstrate that epalrestat ameliorates pulmonary vascular remodeling of PAH rats through down-regulating of TGF-β1and AR expression.