中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (24): 6247-6258.doi: 10.12307/2026.165

• 组织构建实验造模 experimental modeling in tissue construction • 上一篇    下一篇

ABL1蛋白在心肌细胞程序性坏死和心脏缺血再灌注损伤中的作用机制

袁  敏，韩  瑜，刘金红，张竞予，曹济民，孙  腾   

  1. 山西医科大学细胞生理学教育部重点实验室，山西省细胞生理学重点实验室，山西医科大学基础医学院生理学系，山西省太原市   030001
  • 收稿日期:2025-03-26 修回日期:2025-09-03 出版日期:2026-08-28 发布日期:2026-01-30
  • 通讯作者: 孙腾，博士，副教授，博士生导师，山西医科大学细胞生理学教育部重点实验室，山西省细胞生理学重点实验室，山西医科大学基础医学院生理学系，山西省太原市 030001
  • 作者简介:袁敏，女，1997年生，山东省潍坊市人，汉族，山西医科大学在读硕士，主要从事心肌损伤的表观遗传学调控机制研究。
  • 基金资助:
    国家自然科学基金面上项目(82170294)，项目负责人：孙腾；国家自然科学基金青年科学基金项目(81800268)，项目负责人：孙腾；
    国家自然科学基金面上项目(82170523)，项目负责人：曹济民；中央引导地方科技发展资金项目(YDZJSX2022A061)，项目负责人：孙腾；山西省高等教育“百亿工程”科技引导专项(BYJL006)，项目负责人：孙腾

Role and mechanism of ABL1 in myocardial necroptosis and cardiac ischemia/reperfusion injury

Yuan Min, Han Yu, Liu Jinhong, Zhang Jingyu, Cao Jimin, Sun Teng    

  1. Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, and the Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Received:2025-03-26 Revised:2025-09-03 Online:2026-08-28 Published:2026-01-30
  • Contact: Sun Teng, PhD, Associate professor, Doctoral supervisor, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, and the Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • About author:Yuan Min, MS candidate, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, and the Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Supported by:
    National Natural Science Foundation of China (General Program), No. 82170294 (to ST); National Natural Science Foundation of China (Youth Program), No. 81800268 (to ST); National Natural Science Foundation of China (General Program), No. 82170523 (to CJM); The Central Leading Local Science and Technology Development Fund Project, No. YDZJSX2022A061 (to ST); Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project, No. BYJL006 (to ST)

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摘要：



文题释义：
ABL1蛋白：Abelson非受体酪氨酸激酶基因1(Abl1基因)是一种编码非受体酪氨酸激酶的原癌基因，其编码蛋白ABL1参与调控多种细胞过程，包括细胞增殖、分化、黏附以及细胞应激等。有研究表明，敲低ABL1可显著影响缺氧反应、糖酵解等多个关键生物过程。

背景：ABL1蛋白参与调控多种细胞过程，然而它在心血管系统中的功能远远未被揭示，尤其是在心脏缺血/再灌注损伤和程序性坏死中的作用尚未见报道。
目的：探究ABL1蛋白在心脏缺血/再灌注损伤和心肌细胞程序性坏死中的作用及其机制。
方法：①动物实验：使用随机数字表法将C57BL/6J小鼠分成4组，假手术组、缺血/再灌注组、敲低ABL1+缺血/再灌注组、ABL1阴性对   照+缺血/再灌注组，后2组小鼠于心脏原位注射ABL1敲低慢病毒或阴性对照慢病毒，1周后3组缺血/再灌注模型小鼠通过结扎冠状动脉左前降支再恢复血流来建立小鼠心脏缺血/再灌注损伤模型。检测小鼠心脏组织ABL1蛋白表达水平、心功能、心肌纤维化程度和心肌细胞表面积。②细胞实验：将H9c2细胞分为4组，阴性对照细胞系+PBS组、ABL1敲低细胞系+PBS组、阴性对照细胞系+H2O2 500 µmol/L组、ABL1敲低细胞系+H2O2 500 µmol/L组；另将H9c2细胞分为5组：阴性对照细胞系+PBS组、阴性对照细胞系+H2O2 500 µmol/L组、ABL1敲低细胞系+H2O2 500 µmol/L组、ABL1敲低细胞系+Parkin过表达腺病毒+H2O2 500 µmol/L组、ABL1敲低细胞系+Parkin阴性对照腺病毒+H2O2 500 µmol/L组，构建ABL1蛋白敲低细胞系和过氧化氢诱导心肌细胞氧化应激模型。检测细胞活力、细胞程序性坏死水平、活性氧水平及线粒体膜电位，检测细胞ABL1蛋白、Parkin和亲环素D蛋白的表达及ABL1蛋白与Parkin是否组成信号轴。
结果与结论：①小鼠心脏缺血/再灌注模型ABL1蛋白表达水平显著下调；②敲低ABL1蛋白加重缺血/再灌注诱导的心功能障碍，表现为左室射血分数和短轴缩短率的降低、左心室收缩末期内径和舒张末期内径的增大；③敲低ABL1蛋白促进缺血/再灌注诱导的心肌纤维化，加重缺血/再灌注诱导的心室重构；④心肌细胞氧化应激模型ABL1蛋白表达水平显著下调；⑤敲低ABL1蛋白加剧氧化应激诱导的细胞活力下降、程序性坏死以及活性氧积累；⑥ABL1蛋白调控线粒体膜通透性，调控Parkin和亲环素D的表达，并通过靶向Parkin调控细胞的氧化应激水平；⑦结果表明，ABL1蛋白在体内缺血/再灌注模型和体外氧化应激模型中的表达水平均显著下调，敲低ABL1蛋白加剧心脏缺血/再灌注损伤和心肌细胞氧化应激损伤，其通过靶向Parkin-CypD通路发挥这一作用。
https://orcid.org/0009-0008-6471-0227 (袁敏) 


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: ABL1蛋白, 缺血/再灌注损伤, 程序性坏死, 氧化应激, 线粒体膜通透性, Parkin, 亲环素D

Abstract: BACKGROUND: ABL1 is involved in the regulation of multiple cellular processes, yet its functions within the cardiovascular system remains largely unexplored. In particular, its role in cardiac ischemia/reperfusion injury and necroptosis has not been reported.
OBJECTIVE: To investigate the role of ABL1 in cardiac ischemia/reperfusion injury and myocardial necroptosis, as well as the underlying molecular mechanisms.
METHODS: (1) Animal experiment: C57BL/6J mice were randomly divided into four groups: sham surgery group, ischemia/reperfusion group, ABL1 knockdown + ischemia/reperfusion group, and ABL1 negative control + ischemia/reperfusion group. Lentiviral vectors targeting ABL1 were injected in situ into the myocardium to knock down ABL1 expression. One week later, cardiac ischemia/reperfusion injury was induced in mice via ligation of the left anterior descending coronary artery followed by reperfusion. Protein expression of ABL1 in heart tissue was detected. Cardiac function, myocardial fibrosis, and cardiomyocyte surface area were assessed. (2) Cell experiment: H9c2 cells were divided into four groups: negative control cell line + PBS group, ABL1 knockdown cell line + PBS group, negative control cell line + hydrogen peroxide (H₂O₂) 500 µmol/L group, and ABL1 knockdown cell line + H2O2 500 µmol/L group. Another H9c2 cells were divided into five groups: negative control cell line+PBS group, negative control cell line + H₂O₂ 500 µmol/L group, and ABL1 knockdown cell line + H₂O₂ 500 µmol/L group, ABL1 knockdown cell line + Parkin overexpression adenovirus + H₂O₂ 500 µmol/L group, and ABL1 knockdown cell line + Parkin negative control adenovirus+H₂O₂ 500 µmol/L group. ABL1-knockdown cell lines were established. An oxidative stress model was induced using hydrogen peroxide (H₂O₂). Subsequent changes in cell viability, necroptosis levels, and reactive oxygen species level were evaluated. Mitochondrial membrane potential was detected, and the expression levels of ABL1, Parkin and CypD were measured. Whether ABL1 protein and Parkin form a signaling axis was detected.
RESULTS AND CONCLUSION: (1) ABL1 expression was significantly down-regulated in the mouse model of cardiac ischemia/reperfusion. (2) Knockdown of ABL1 exacerbated ischemia/reperfusion-induced cardiac dysfunction, as evidenced by reduced left ventricular ejection fraction and fractional shortening, along with increased left ventricular end-systolic and end-diastolic diameters. (3) Knockdown of ABL1 promoted ischemia/reperfusion-induced myocardial fibrosis and aggravated ischemia/reperfusion-induced ventricular remodeling. (4) ABL1 expression was significantly downregulated in the cardiomyocyte oxidative stress model. (5) Knockdown of ABL1 exacerbated oxidative stress-induced reductions in cell viability, increases in necroptosis, and reactive oxygen species accumulation. (6) ABL1 regulated mitochondrial membrane permeability, influenced the expression of Parkin and CypD, and modulated cellular oxidative stress levels by targeting Parkin. In conclusion, ABL1 expression is significantly reduced in both in vivo ischemia/reperfusion models and in vitro oxidative stress models. Furthermore, ABL1 knockdown exacerbates cardiac ischemia/reperfusion injury and oxidative stress-induced cardiomyocyte damage by targeting the Parkin-CypD signaling pathway. 

Key words: ABL1, ischemia-reperfusion injury, necroptosis, oxidative stress, mitochondrial membrane permeability, Parkin, CypD

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