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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 investigate the effect of proteasome inhibitor PS-341 on the expression of Nrf2 and NF-κB in pulmonary arteries of hypertensive pulmonary hypertension (PAH) rats and its possible role mechanism. Methods 48 female Wistar rats were randomly divided into saline control group, PS-341 control group, saline shunt group and PS-341 treatment group. Control group sham operation, shunt group abdominal aorta - inferior vena cava fistula surgery. Three days after operation, 50μg / kg of PS-341 or equal volume of saline was given twice a week for 8 weeks. The indexes of hemodynamics and lung morphology were measured and HE staining was performed. The expression of Nrf2, NF-κB-P65, Nqo1 and MMP-2 in pulmonary arteries were detected by immunohistochemistry, RT-PCR and Western blotting. Results Compared with the control group, the pulmonary artery wall thickening, lumen stenosis, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), WT% and WA% increased significantly in the shunt group (all P <0.05 ), And the expression of Nrf2, NF-κB, Nqo1 and MMP-2 increased (P <0.05). Compared with the shunt group, PS-341 significantly attenuated the pulmonary artery wall thickening and lumen stenosis, decreased RVSP, RVHI, WT% and WA% (P <0.05), NF-κB and MMP- 2 activity was inhibited, while Nrf2 and Nqo1 expression was significantly enhanced (P <0.05). Conclusion PS-341 may delay the vascular remodeling of pulmonary hypertension by promoting the expression of Nrf2 gene and Nqo1 and inhibiting the expression of NF-κB and MMP-2.