中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (25): 5351-5361.doi: 10.12307/2025.508

• 干细胞培养与分化 stem cell culture and differentiation • 上一篇    下一篇

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

张国安1，石  践1，宋宝国1，黄晓燕2   

  1. 陕西省人民医院，1心血管外科，2陕西省感染与免疫重点实验室，陕西省西安市   710068
  • 收稿日期:2024-01-20 接受日期:2024-04-19 出版日期:2025-09-08 发布日期:2024-12-24
  • 通讯作者: 黄晓燕，硕士，副主任医师，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
  • 作者简介:张国安，男，1983年生，2007年西安交通大学医学院毕业，硕士，主治医师，主要从事心血管外科方向研究。
  • 基金资助:
    陕西省重点研发计划项目(2023-YBSF-672)，项目负责人：石践

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

Zhang Guoan1, Shi Jian1, Song Baoguo1, Huang Xiaoyan2   

  1. 1Department of Cardiovascular Surgery, 2Shaanxi Provincial Key Laboratory of Infection and lmmune Diseases, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
  • Received:2024-01-20 Accepted:2024-04-19 Online:2025-09-08 Published:2024-12-24
  • Contact: Huang Xiaoyan, Master, Associate chief physician, Shaanxi Provincial Key Laboratory of Infection and lmmune Diseases, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
  • About author:Zhang Guoan, Master, Attending physician, Department of Cardiovascular Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
  • Supported by:
    Shaanxi Province Key Research & Development Plan Project, No. 2023-YBSF-672 (to SJ)

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摘要：

文题释义：

B细胞淋巴瘤2相关蛋白A1(B-cell lymphoma 2-related protein A1，BCL2A1)：为BCL2蛋白家族成员，该家族的蛋白质形成异二聚体或同二聚体，并作为抗凋亡和促凋亡调节因子，参与多种细胞活动，如胚胎发育、肿瘤发生。BCL2A1编码的蛋白能减少线粒体前凋亡细胞色素c的释放，阻断Caspase的激活。此外，该基因也是核因子κB响应炎症递质的直接转录靶标，可被不同的细胞外信号上调。
组蛋白脱乙酰酶1基因(histone deacetylase 1 gene，HDAC1)：是一种蛋白质编码基因。该基因由多亚基复合物催化的组蛋白乙酰化和脱乙酰化，并在真核基因表达调控中发挥着关键作用。HDAC1编码的蛋白质属于组蛋白脱乙酰酶/acuc/apha家族，是组蛋白脱乙酰酶复合物的组成部分。此外，它还与转移相关蛋白2共同使p53脱乙酰化并调节细胞生长和凋亡。

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200 μg/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1.5 μg/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500 μL 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。

https://orcid.org/0000-0003-0056-0166 (黄晓燕) 


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 动脉粥样硬化, BCL2A1, HDAC1, 乙酰化, 细胞焦亡

Abstract: 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 200 μg/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 1.5 μg/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. 500 μL 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 low-density 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 umbilical vein endothelial cells by deacetylating BCL2A1 to reduce atherosclerosis and inflammatory response.

Key words: atherosclerosis, BCL2A1, HDAC1, acetylation, cell pyroptosis

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