[1]李若愚,杨勤宇,程翠云,等.血管生成素样蛋白2通过调控磷脂酰肌醇3-激酶/蛋白激酶B /哺乳动物雷帕霉素靶蛋白通路抑制血管平滑肌细胞自噬加重冠心病的实验研究[J].陕西医学杂志,2026,(7):894-901,945.[doi:DOI:10.3969/j.issn.1000-7377.2026.07.005]
　LI Ruoyu,YANG Qinyu,CHENG Cuiyun,et al.Experimental study on the aggravation of coronary heart disease by ANGPTL2 inhibiting autophagy in vascular smooth muscle cells through regulating the PI3K/Akt/mTOR pathway[J].,2026,(7):894-901,945.[doi:DOI:10.3969/j.issn.1000-7377.2026.07.005]
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血管生成素样蛋白2通过调控磷脂酰肌醇3-激酶/蛋白激酶B /哺乳动物雷帕霉素靶蛋白通路抑制血管平滑肌细胞自噬加重冠心病的实验研究

《陕西医学杂志》[ISSN:1000-7377/CN:61-1281/TN]

卷:
期数:
2026年7期
页码:
894-901,945
栏目:
基础研究
出版日期:
2026-07-05

文章信息/Info

Title:
Experimental study on the aggravation of coronary heart disease by ANGPTL2 inhibiting autophagy in vascular smooth muscle cells through regulating the PI3K/Akt/mTOR pathway
作者:
李若愚1; 杨勤宇1; 程翠云2; 杜睿1; 周吟波1
(1.都江堰市人民医院心血管内科，四川 都江堰611830;2.四川省人民医院药学部，四川 成都 610000)
Author(s):
LI Ruoyu1; YANG Qinyu1; CHENG Cuiyun2; DU Rui1; ZHOU Yinbo1
（1.Department of Cardiovascular Medicine,Dujiangyan People’s Hospital,Dujiangyan 611830，China;2.Department of Pharmacy,Sichuan Provincial People’s Hospital,Chengdu 610000,China）
关键词:
冠心病; 血管生成素样蛋白2; 磷脂酰肌醇3-激酶/蛋白激酶B /哺乳动物雷帕霉素靶蛋白通路; 血管平滑肌细胞; 自噬; 炎症反应
Keywords:
Coronary heart disease; Angiopoietin-like protein 2; PI3K/Akt/mTOR pathway; Vascular smooth muscle cells; Autophagy; Inflammatory response
分类号:
R 541.4
DOI:
DOI:10.3969/j.issn.1000-7377.2026.07.005
文献标志码:
A
摘要:
目的：探讨血管生成素样蛋白2（ANGPTL2）调控磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）通路对血管平滑肌细胞（VSMCs）自噬的影响，及其介导冠心病发生的作用机制。方法：使用ox-LDL（100 μg/ml）处理VSMCs，体外构建动脉粥样硬化相关细胞模型，转染ANGPTL2小干扰RNA（si-ANGPTL2）和过表达载体（pcDNA-ANGPTL2）；分析ANGPTL2对VSMCs增殖、迁移、炎症反应[肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）]和自噬相关蛋白[微管相关蛋白1轻链3-Ⅱ/微管相关蛋白1轻链3-Ⅰ（LC3-Ⅱ/LC3-Ⅰ）、Beclin 1]表达的影响。使用PI3K激活剂740 YP处理转染si-ANGPTL2的VSMCs，分析PI3K/Akt/mTOR通路是否参与VSMCs的自噬过程。通过ApoE-/-小鼠构建冠心病小鼠模型，尾静脉注射ANGPTL2干扰慢病毒敲低其表达；检测小鼠心脏组织中PI3K/Akt/mTOR通路相关蛋白及自噬相关蛋白表达水平；分析敲低ANGPTL2对小鼠脂质和炎症水平的改善作用。结果：体外细胞实验：①ox-LDL处理的VSMCs中，ANGPTL2蛋白表达明显升高，且ox-LDL 处理促进了VSMCs的异常增殖、迁移和炎症因子表达，抑制自噬相关蛋白表达（均P<0.05）；②沉默ANGPTL2抑制了VSMCs的增殖、迁移和炎症，并促进自噬发生（均P<0.05）；③740 YP处理能够减弱沉默ANGPTL2对PI3K/Akt/mTOR通路及自噬相关蛋白表达的影响（均P<0.05）。体内小鼠模型：①冠心病模型小鼠心脏组织中ANGPTL2表达显著升高（P<0.05）；②干扰ANGPTL2表达明显抑制了模型小鼠心脏组织中PI3K/Akt/mTOR通路相关蛋白表达，并逆转自噬相关蛋白表达，促进自噬发生（均P<0.05）；③干扰ANGPTL2表达可明显改善模型小鼠血脂总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）和高密度脂蛋白（HDL）水平，抑制炎症因子TNF-α、IL-6和IL-1β 表达（均P<0.05）。结论：ANGPTL2可能通过激活PI3K/AKt/mTOR通路，抑制VSMCs的自噬，并促进VSMCs的异常增殖、迁移和炎症反应，促进动脉粥样硬化发生；干扰ANGPTL2表达可抑制 PI3K/Akt/mTOR通路，减轻冠心病小鼠心脏病理损伤，改善血脂水平。
Abstract:
Objective:To explore the effect of angiopoietin-like protein 2 (ANGPTL2) regulating the PI3K/Akt/mTOR pathway on autophagy in vascular smooth muscle cells (VSMCs) and its mechanism of mediating the occurrence of coronary heart disease.Methods：VSMCs were treated with ox-LDL (100 μg/ml),and atherosclerotic related cell models were constructed in vitro.ANGPTL2 small interfering RNA (si-ANGPTL2) and overexpression vector (pcDNA-ANGPTL2) were transfected;To analyze the effects of ANGPTL2 on the proliferation,migration,inflammatory response （TNF-α、 IL-6 and IL-1β） and the expression of autophagy-related proteins (LC3-Ⅱ/LC3-Ⅰ、 Beclin 1) of VSMCs.VSMCs transfected with si-ANGPTL2 were treated with PI3K activator 740 YP to analyze whether the PI3K/Akt/mTOR pathway is involved in the autophagy process of VSMCs.A mouse model of coronary heart disease was established in ApoE-/- mice,and ANGPTL2 was injected into the tail vein to interfere with lentivirus knockdown and reduce its expression;Detect the expression levels of PI3K/Akt/mTOR pathway-related proteins and autophagy-related proteins in the cardiac tissues of mice;To analyze the improvement effect of knockdown ANGPTL2 on lipid and inflammatory levels in mice.Results:In vitro cell experiments：① In VSMCs treated with ox-LDL,the expression of ANGPTL2 protein was significantly increased,and ox-LDL treatment promoted the abnormal proliferation,migration and expression of inflammatory factors in VSMCs,while inhibiting the expression of autophagy-related proteins(all P<0.05);② Silencing ANGPTL2 inhibited the proliferation,migration and inflammation of VSMCs,and promoted autophagy (all P<0.05);③740 YP treatment could weaken the effect of silencing ANGPTL2 on the PI3K/Akt/mTOR pathway and the expression of autophagy-related proteins (all P<0.05).In vivo mouse models：①The expression of ANGPTL2 in the cardiac tissues of mice with coronary heart disease models was significantly increased(P<0.05);②Interfering with the expression of ANGPTL2 significantly inhibited the expression of PI3K/Akt/mTOR pathpath-related proteins in the cardiac tissue of model mice,reversed the expression of autophagy-related proteins,and promoted the occurrence of autophagy(all P<0.05);③ Interference with the expression of ANGPTL2 can significantly improve the levels of TC,TG,LDL and HDL in blood lipids of model mice,and inhibit the expression of inflammatory factors TNF-α,IL-6 and IL-1β(allP<0.05).Conclusion:ANGPTL2 may inhibit autophagy of VSMCs by activating the PI3K/AKt/mTOR pathway,and promote abnormal proliferation,migration and inflammatory response of VSMCs,which can promote the occurrence of atherosclerosis.Interfering with the expression of ANGPTL2 can inhibit the PI3K/Akt/mTOR pathway,alleviate cardiac pathological damage in mice with coronary heart disease,and improve blood lipid levels.

参考文献/References:

[1]FAN J，WATANABE T.Atherosclerosis：Known and unknown[J].Pathol Int，2022，72（3）：151-160.
[2]刘宁，艾英，刘健.芦黄颗粒联合单硝酸异山梨酯治疗冠心病不稳定型心绞痛疗效及对患者心功能与脂代谢的影响[J].陕西中医，2023，44（1）：64-67.
[3]CHEN Z，OUYANG C，ZHANG H，et al.Vascular smooth muscle cell-derived hydrogen sulfide promotes atherosclerotic plaque stability via TFEB (transcription factor EB)-mediated autophagy[J].Autophagy，2022，18（10）：2270-2287.
[4]PI S，MAO L，CHEN J，et al.The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis[J].Autophagy，2021，17（4）：980-1000.
[5]TAKANO M，HIROSE N，SUMI C，et al.ANGPTL2 promotes inflammation via integrin α5β1 in chondrocytes[J].Cartilage，2021，13（2）：885s-897s.
[6]LABBE P，MUNOZ GOYETTE V，THORIN-TRESCASES N，et al.Angiopoietin-like 2 is essential to aortic valve development in mice[J].Commun Biol，2022，5（1）：1277.
[7]YANG H，LIU J，CHEN X，et al.Angptl2 gene knockdown is critical for abolishing angiotensin Ⅱ-induced vascular smooth muscle cell proliferation and migration[J].Biochem Cell Biol，2022，100（1）：59-67.
[8]CHEN W，WANG J，WANG X，et al.Knockdown of hypoxia-inducible factor 1-alpha (HIF1α) interferes with angiopoietin-like protein 2 (ANGPTL2) to attenuate high glucose-triggered hypoxia/reoxygenation injury in cardiomyocytes[J].Bioengineered，2022，13（1）：1476-1490.
[9]王伊凡，李思远，张姣.右美托咪定预处理通过PI3K/Akt/mTOR信号通路对心肌缺血再灌注大鼠心脏损伤和心肌组织自噬的影响[J].陕西医学杂志，2023，52（10）：1299-1303.
[10]LI R，ZHENG Y，ZHANG J，et al.Gomisin N attenuated cerebral ischemia-reperfusion injury through inhibition of autophagy by activating the PI3K/AKT/mTOR pathway[J].Phytomedicine，2023，110：154644.
[11]TANG H Y，CHEN A Q，ZHANG H，et al.Vascular Smooth muscle cells phenotypic switching in cardiovascular diseases[J].Cells，2022，11（24）：4060.
[12]WORSSAM M D，JORGENSEN H F.Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases[J].Biochem Soc Trans，2021，49（5）：2101-2111.
[13]ZHU Y，TIAN X，WANG Y，et al.Inhibition of lncRNA NFIA-AS1 alleviates abnormal proliferation and inflammation of vascular smooth muscle cells in atherosclerosis by regulating miR-125a-3p/AKT1 axis[J].Int J Genomics，2023，2023：8437898.
[14]LIN H H，HSIEH M C，WANG C P，et al.Anti-atherosclerotic effect of gossypetin on abnormal vascular smooth muscle cell proliferation and migration[J].Antioxidants (Basel)，2021，10（9）：1357.
[15]李霞，王景梅，李军华，等.血清miR-124、CD146及Angptl2水平与急性脑梗死患者颈动脉粥样硬化斑块稳定性的关系研究[J].国际检验医学杂志，2024，45（17）：2121-2126,2131.
[16]HANG J.Biomarkers of endothelial activation and dysfunction in cardiovascular diseases[J].Rev Cardiovasc Med，2022，23（2）：73.
[17]LABBE P，MARTEL C，SHI Y F，et al.Knockdown of ANGPTL2 promotes left ventricular systolic dysfunction by upregulation of NOX4 in mice[J].Front Physiol，2024，15：1320065.
[18]杜华，李杰.冠心病患者血清中MMP-9、Angptl2、炎症因子与患者CT下斑块性质及预后的关系[J].实验与检验医学，2023，41（2）：136-138，152.
[19]ZROBICHAUD S,RASHEED A,PIETRANGELO A,et al.Autophagy is differentially regulated in leukocyte and nonleukocyte foam cells during atherosclerosis[J].Circ Res，2022，130（6）：831-847.
[20]LU Q，YAO Y，HU Z，et al.Angiogenic factor Aggf1 activates autophagy with an essential role in therapeutic angiogenesis for heart disease[J].PLoS Biol，2016，14（8）：e1002529.
[21]TANG Z L，ZHANG K，LV S C，et al.LncRNA MEG3 suppresses PI3K/AKT/mTOR signalling pathway to enhance autophagy and inhibit inflammation in TNF-α treated keratinocytes and psoriatic mice[J].Cytokine，2021，148：155657.
[22]LIU C，CHEN G，CHEN Y，et al.Danlou tablets inhibit atherosclerosis in apolipoprotein E-Deficient mice by inducing macrophage autophagy：The role of the PI3K-Akt-mTOR pathway[J].Front Pharmacol，2021，12：724670.
[23]LI F，PENG J，LU Y，et al.Blockade of CXCR4 promotes macrophage autophagy through the PI3K/AKT/mTOR pathway to alleviate coronary heart disease[J].Int J Cardiol，2023，392：131303.

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备注/Memo

备注/Memo:
四川省科技计划项目（2024SF0659）
更新日期/Last Update: 2026-07-10