缺氧诱导因子1α通过介导铁死亡影响动脉粥样硬化的机制研究  

Mechanism of Hypoxia-Inducing Factor 1αInfluencing Atherosclerosis Mediated by Ferroptosis

作　　者：蔡荟芝 罗玲[1] CAI Huizhi;LUO Ling(Department of Cardiology,the First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710000,China)

机构地区：[1]西安交通大学第一附属医院心血管内科,陕西省西安市710000

出　　处：《实用心脑肺血管病杂志》2024年第3期70-76,共7页Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease

基　　金：陕西省自然科学基金资助项目(2021JM-419)。

摘　　要：目的探讨缺氧诱导因子1α(HIF-1α)通过介导铁死亡影响动脉粥样硬化的机制。方法本实验时间为2022年2月—2023年6月。人体试验:选取西安交通大学第一附属医院收治的6例行颈动脉内膜切除术的颈动脉粥样硬化患者的手术标本为颈动脉粥样硬化组,6例因糖尿病动脉闭塞所致下肢坏死而截肢者的手术标本为糖尿病动脉闭塞组,6例下肢动脉粥样硬化患者的手术标本为下肢动脉粥样硬化组,6例先天性四肢动静脉瘘患者的手术标本为正常组。对四组手术标本进行苏木素-伊红(HE)染色、油红O染色、透射电子显微镜检查,采用Western blotting法检测谷胱甘肽过氧化物酶4(GPX4)、HIF-1α表达水平。动物实验:选取ApoE^(-/-)C57BL/6小鼠18只,采用简单随机法将小鼠分为对照组、高脂肪饮食(HFD)组、PX-478组,每组6只。对照组小鼠采用正常饲料喂养;HFD组和PX-478组小鼠采用HFD连续喂养5个月。之后PX-478组小鼠给予PX-4785 mg·kg^(-1)·d^(-1),每2 d腹腔注射1次;对照组和HFD组小鼠给予等量0.9%氯化钠溶液,每2 d腹腔注射1次,均连续给药2个月。腹腔注射结束后处死小鼠,取其主动脉。对三组小鼠主动脉窦进行HE染色、油红O染色、Russell-Movall五色染色,采用Western blotting法检测HIF-1α表达水平。细胞实验:选取THP-1细胞并诱导其向巨噬细胞分化,将THP-1巨噬细胞分为THP-1巨噬细胞组、氧化型低密度脂蛋白(ox-LDL)组和ox-LDL+PX-478组,其中ox-LDL组加入ox-LDL并孵育48 h,ox-LDL+PX-478组加入ox-LDL和PX-478并孵育48 h。采用Western blotting法检测GPX4、HIF-1α表达水平,采用Mito-Tracker染色法计数活性氧(ROS)阳性细胞数,测定铁含量、谷胱甘肽(GSH)水平。结果人体试验结果:HE染色结果显示,与正常组相比,颈动脉粥样硬化组、糖尿病动脉闭塞组和下肢动脉粥样硬化组动脉中可见内膜增厚、纤维帽和核心坏死的动脉粥样硬化斑块。油红O染色结�Objective To investigate the mechanism of hypoxia-inducing factor 1α(HIF-1α)influencing atherosclerosis mediated by ferroptosis.Methods The experiment time was from February 2022 to June 2023.Human trial:6 surgical specimens from patients with carotid atherosclerosi undergoing carotid endarterectomy and admitted to the First Affiliated Hospital of Xi'an Jiaotong University were selected as the carotid atherosclerosis group,6 surgical specimens from patients with amputation due to lower limb necrosis caused by diabetes artery occlusion were selected as the diabetes artery occlusion group,6 surgical specimens from patients with lower extremity atherosclerosis were selected as the lower extremity atherosclerosis group,6 surgical specimens from patients with congenital arteriovenous fistula in the limbs were selected as the normal group.Surgical specimens in four groups were subjected to hematoxylin-eosin(HE)staining,oil red O staining,and transmission electron microscopy examination,Western blotting method was used to detect glutathioneperoxidase 4(GPX4)and HIF-1αexpression levels.Animal experiment:18 C57BL/6 mice with ApoE^(-/-)were selected and divided into the control group,the high fat diet(HFD)group,and the PX-478 group by simple randomization,with 6 mice in each group.The mice in control group were fed with normal feed;the mice in HFD group and PX-478 group were continuously fed with HFD for 5 months.Afterwards,the mice in PX-478 group were given PX-4785 mg·kg^(-1)·d^(-1),intraperitoneal injection every 2 days;the mice in control group and HFD group were given an equal amount of 0.9%sodium chloride solution,intraperitoneal injection every 2 days,administered continuously for 2 months.After intraperitoneal injection,the mice were euthanized and their aortas were taken.Aortic sinus of mite in 3 groups were subjected to HE staining,oil red O staining,and Russell-Movall five color staining,Western blotting method was used to detect HIF-1αexpression level.Cell experiment:THP-1 cells were selected and induced

关 键 词：动脉粥样硬化 缺氧诱导因子1Α 铁死亡 

分 类 号：R543.5[医药卫生—心血管疾病]