摘要
目的探讨蛋白酶体抑制剂PS-341对高血流性肺动脉高压(PAH)大鼠肺血管内核因子E2相关因子2(Nrf2)、核因子-kappa B(NF-κB)活性的影响及其可能作用机制。方法将48只雌性Wistar大鼠随机分为生理盐水对照组、PS-341对照组、生理盐水分流组、PS-341治疗组。对照组行假手术,分流组行腹主动脉-下腔静脉造瘘术。术后3 d分别给予50μg/kg的PS-341或等体积的生理盐水,2次/周,共8周。测量血流动力学、肺形态学指标并进行HE染色;免疫组化、RT-PCR和Western blotting检测肺血管Nrf2、NF-κB-P65、Nqo1和MMP-2的表达水平。结果与对照组相比,分流组大鼠肺动脉管壁明显增厚、管腔狭窄,右心室平均收缩压(RVSP)、右心室肥厚指数(RVHI)及WT%、WA%增高(P均<0.05),且Nrf2、NF-κB、Nqo1及MMP-2表达增强(P<0.05)。PS-341干预后,与分流组相比,大鼠肺动脉管壁增厚及管腔狭窄程度明显减轻,RVSP、RVHI、WT%及WA%水平降低(P<0.05),NF-κB和MMP-2活性受抑制,而Nrf2和Nqo1表达明显增强(P<0.05)。结论 PS-341可能通过促进Nrf2基因及Nqo1的表达,同时抑制NF-κB及MMP-2的表达,延缓高肺血流性肺动脉高压的血管重构。
Objective To explore the effects and potential mechanism of PS-341 on nuclear factor E2-realated factor 2 （ Nrf2 ） and nuclear factor-kappa B （NF-KB） in remodeling vascular of rats with high-flow pulmonary arterial hyperten- sion （PAH）. Methods Forty-eight female Wistar rats were randomly assigned to the vehicle/sham group, PS-341/ sham group, vehicle/shunt group, and PS-341-treated group. The model of aorto-caval shunting （ACS） was established by surgical methods to produce a high blood flow-induced pulmonary hypertension rats. The vehicle/sham and PS-341/ sham groups performed the sham operation. After operation for 3 days, the rats received an intraperitoneal injection of PS-341 （50 μg/kg · d） or vehicle for 8 weeks. The hemodynamic data and right ventricular injury were evaluated. The protein expressions of NF-KB, Nrf2, Nqol and MMP-2 were analyzed by immunohistochemisty and Western blotting. RT-PCR analysis was performed to detect the mRNA expression level of NF-KB. Results Compared with the vehicle/ sham group, the vehicle/shunt group had the higher levels of the right ventricular systolic pressure （ RVSP）, right ven-tricular hypertrophy index （ RVHI）, WT% and WA% （ P 〈 0.05 ）, and the expressions of Nrf2, NF-KB-P65, Nqol and MMP-2 increased （P 〈 0.05 ）. Compared with the vehicle/sham group, the PS-341-treated group deceased the lev- els of RVSP, RVHI, WT% and WA% （ P 〈 0.05 ）, and the activation of NF-KB-P65 and MMP-2 were inhibited, but the expressions of Nrf2 and Nqol significantly increased （P 〈 0.05 ）. Conclusion PS-341 might delay vascular re- modeling of high-flow PAH through promoting the expressions of Nrf2 and Nqol, and inhibiting the expressions of NF- KB and MMP-2.
出处
《山东大学学报（医学版）》
CAS
北大核心
2014年第2期6-11,共6页
Journal of Shandong University:Health Sciences
基金
山东省自然科学基金(ZR2011HM078)
