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

作　　者：郑磊 张振希 季润 赵飙 刘雨彤 蔡晶 乔彤[1] Zheng Lei;Zhang Zhenxi;Ji Run;Zhao Biao;Liu Yutong;Cai Jing;Qiao Tong(Department of Vascular Surgery,Nanjing Drum Tower Hospital,the Afiliated Hospital of Nanjing University Medical School,Nanjing 210008,China;Department of Vascular Surgery,Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210008,China)

机构地区：[1]南京大学医学院附属鼓楼医院血管外科,南京210008 [2]南京中医药大学中西医结合鼓楼临床医学院血管外科,南京210008

出　　处：《中华实验外科杂志》2024年第10期2234-2237,共4页Chinese Journal of Experimental Surgery

基　　金：国家自然科学基金(818870348、82200543);江苏省卫生健康委医学科研项目(ZD2021056)。

摘　　要：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.

关 键 词：动脉粥样硬化 低剪应力 血管内皮细胞 低氧诱导因子-1Α PX-478 

分 类 号：R543.5[医药卫生—心血管疾病]