PX-478对低剪应力诱导血管内皮细胞炎性反应的效应机制

Study on the mechanism of PX-478 in treating low shear stress-induced inflammation in vascular endothelial cells

目的:探讨低氧诱导因子-1α(HIF-1α)特异性抑制剂PX-478能否抑制低剪应力(LWSS)诱导的动脉粥样硬化。方法:人脐静脉内皮细胞分为:高剪应力组(HWSS)、LWSS组和LWSS+PX-478组,检测HIF-1α和下游基因表达。C57BL6雄性小鼠腹腔注射PX-478,检测动脉内皮细胞HIF-1α表达。对Apoe-/-小鼠部分(颈内动脉、颈外动脉、枕动脉)颈动脉结扎,腹腔注射PX-478,观察颈动脉HIF-1α和炎症分子表达以及颈动脉粥样硬化。组间比较采用t检验。结果:PX-478组HIF-1α表达(3.380±0.388比22.200±1.458,t=6.057,P<0.01)低于DMSO组。PCAL组内皮细胞炎症(955.661±172.953比15.200±3.384,t=5.437,P<0.01)和动脉粥样硬化程度(39.739±1.683比6.020±0.766,t=18.24,P<0.01)重于对照组,PCAL+PX-478组动脉内皮细胞炎症(163.978±15.035比955.661±172.953,t=4.560,P<0.01)与动脉粥样硬化程度(16.847±1.584比39.739±1.683,t=9.905,P<0.01)轻于PCAL组。结论:PX-478降低LWSS诱导的HIF-1α表达,缓解内皮细胞炎症,抑制动脉粥样硬化的发生。

Objective:To investigate whether PX-478,a specific inhibitor of Hypoxia inducible factor-1α(HIF-1α),could inhibit the development of atherosclerosis(AS)induced by low wall shear stress(LWSS).Methods:Human Umbilical Vein Endothelial Cells(HUVECs)were divided into four groups:High wall shear stress(HWSS)group,LWSS group,and LWSS+PX-478 group.The expression of HIF-1αand its downstream genes was detected.Male C57BL6 mice were intraperitoneally injected with PX-478 to detect the expression of HIF-1αin endothelial cells.Apoe-/-mice were subjected to artery ligation of internal carotid artery,external carotid artery and occipital artery,followed by PX-478 treatment to observe the expression of HIF-1α,inflammation molecule and severity of AS in carotid artery.Comparisons among groups were made using t-tests.Results:Treat with PX-478 reduces the expression of HIF-1α(22.235±1.458 vs.3.380±0.388,t=6.057,P<0.01)compared with DMSO group in HUVECs.In PX-478 group,the expression of HIF-1α(3.380±0.388 vs.22.200±1.458,t=6.057,P<0.01)was lower than DMSO group.In PCAL group,endothelial cell inflammation(955.661±172.953 vs.15.2±3.384,t=5.437,P<0.01)and atherosclerosis(39.739±1.683 vs.6.020±0.766,t=18.24,P<0.01)were higher than control group.In PCAL+PX-478 group,endothelial cell inflammation(163.978±15.035 vs.955.661±172.953,t=4.560,P<0.01)and the degree of atherosclerosis(16.847±1.584 vs.39.739±1.683,t=9.905,P<0.01)were lower than PCAL group.Conclusion:PX-478 could alleviate endothelial cell inflammation by inhibiting expression of HIF-1αand occurrence of atherosclerosis induced by LWSS.