组蛋白脱乙酰酶1基因抑制人脐静脉内皮细胞焦亡并减轻动脉粥样硬化及炎性反应  

Histone deacetylase 1 gene inhibits pyroptosis of human umbilical vein endothelial cells and alleviates atherosclerosis and inflammatory response

作　　者：张国安[1] 石践[1] 宋宝国[1] 黄晓燕[2] Zhang Guoan;Shi Jian;Song Baoguo;Huang Xiaoyan(Department of Cardiovascular Surgery,Shaanxi Provincial People’s Hospital,Xi’an 710068,Shaanxi Province,China;Shaanxi Provincial Key Laboratory of Infection and lmmune Diseases,Shaanxi Provincial People’s Hospital,Xi’an 710068,Shaanxi Province,China)

机构地区：[1]陕西省人民医院心血管外科,陕西省西安市710068 [2]陕西省人民医院陕西省感染与免疫重点实验室,陕西省西安市710068

出　　处：《中国组织工程研究》2025年第25期5351-5361,共11页Chinese Journal of Tissue Engineering Research

基　　金：陕西省重点研发计划项目(2023-YBSF-672),项目负责人:石践。

摘　　要：背景:细胞焦亡作为炎症细胞死亡的一种独特形式,在动脉粥样硬化病变的不稳定性中发挥重要作用。目的:探究重组B细胞淋巴瘤2相关蛋白A1(B-cell lymphoma 2-related protein A1,BCL2A1)在动脉粥样硬化中的作用机制。方法:①使用200μg/mL氧化低密度脂蛋白处理人脐静脉内皮细胞24 h以诱导内皮损伤。随后,分别使用50 nmol/L BCL2A1干扰质粒(sh-BCL2A1)和1.5μg/mL组蛋白脱乙酰酶1基因(histone deacetylase 1 gene,HDAC1)过表达载体(pcDNA-HDAC1)转染人脐静脉内皮细胞,或同时转染pcDNA-HDAC1和BCL2A1过表达载体(pcDNA-BCL2A1)。转染后培养48 h检测BCL2A1和HDAC1的表达水平、细胞活力、细胞焦亡水平以及BCL2A1乙酰化水平。②通过高脂喂养APOE-/-小鼠构建动脉粥样硬化小鼠模型进行体内验证。将500μL BCL2A1和HDAC1慢病毒过表达载体分别或同时尾静脉注射到小鼠体内,检测BCL2A1和HDAC1的表达水平以及小鼠动脉组织损伤情况。结果与结论:氧化低密度脂蛋白诱导的人脐静脉内皮细胞中BCL2A1上调,干扰BCL2A1可改善细胞活力并抑制细胞焦亡和炎症反应。此外,氧化低密度脂蛋白诱导的人脐静脉内皮细胞中HDAC1下调,通过促进BCL2A1去乙酰化提高了细胞活力及抑制了细胞焦亡和炎症反应。体内实验表明,BCL2A1在高脂喂养的小鼠动脉组织中高表达,而HDAC1低表达。此外,HDAC1通过促进BCL2A1去乙酰化减轻了高脂喂养诱导的ApoE-/-小鼠动脉组织病变。结果表明,HDAC1可能通过BCL2A1去乙酰化来抑制人脐静脉内皮细胞焦亡进而减轻动脉粥样硬化和炎症反应。BACKGROUND:Pyroptosis,as a unique form of inflammatory cell death,plays an important role in the instability of atherosclerotic lesions.OBJECTIVE:To explore the action mechanism of recombinant B-cell lymphoma 2-related protein A1(BCL2A1)in atherosclerosis.METHODS:(1)Human umbilical vein endothelial cells were treated with 200μg/mL oxidized low-density lipoprotein for 24 hours to induce endothelial injury.Subsequently,50 nmol/L BCL2A1 interfering plasmid(BCL2A1 short hairpin RNA,sh-BCL2A1)and 1.5μg/mL histone deacetylase 1 gene(HDAC1)overexpression vector(pcDNA-HDAC1)was transfected into human umbilical vein endothelial cells,or both pcDNA-HDAC1 and BCL2A1 overexpression vector(pcDNA-BCL2A1)were transfected simultaneously.After 48 hours of cell culture,the expression levels of BCL2A1 and HDAC1,cell viability,cell pyroptosis level,and BCL2A1 acetylation level were detected.(2)The atherosclerosis mouse model was constructed by high-fat feeding APOE-/-mouse for in vivo verification.500μL of BCL2A1 and HDAC1 lentiviral overexpression vectors were injected into mice via tail vein,respectively or simultaneously.The expression levels of BCL2A1 and HDAC1 and the damage of arterial tissue in mice were detected.RESULTS AND CONCLUSION:The expression of BCL2A1 was upregulated in human umbilical vein endothelial cells induced by oxidized low-density lipoprotein.Interference of BCL2A1 improved cell viability and inhibited pyroptosis and inflammatory response.In addition,HDAC1 was down-regulated in oxidized lowdensity lipoprotein-induced human umbilical vein endothelial cells.Cell viability was elevated and pyroptosis and inflammatory response were inhibited by promoting BCL2A1 deacetylation.In vivo experiments showed that BCL2A1 was highly expressed in arterial tissues of mice fed with high-fat diet,while HDAC1 was lowly expressed.Additionally,HDAC1 alleviated high-fat diet-induced arterial tissue lesions in ApoE-/-mice by promoting the deacetylation of BCL2A1.It is concluded that HDAC1 may inhibit pyroptosis of human umbili

关 键 词：动脉粥样硬化 BCL2A1 HDAC1 乙酰化 细胞焦亡 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R364.5