自噬与缺血性脑血管疾病的研究进展

doi:10.3760/cma.j.cn441417-20240621-08008

摘要/Abstract

摘要：

缺血性脑血管疾病（ICVD）是一种严重危害人类健康的疾病，具有发病急、致残与致死率高的特点。近年来，ICVD发病率逐年上升，且发病年龄愈发年轻化。自噬为真核生物所特有的一种自我修复过程的生命现象，是细胞内溶酶体降解吞噬物的生理过程。研究发现，缺血性脑损伤后可以激活自噬，从而影响蛋白质表达及内环境，进而加速或阻止ICVD的进程。自噬的双面性目前研究尚不明确，适度调控自噬激活可能是发挥自噬保护作用的关键。本文从ICVD、自噬相关内容及自噬在ICVD中可能的保护和损伤作用展开论述，以期为ICVD诊治提供新方案和新靶点。

关键词:

自噬, 动脉粥样硬化, 信号通路, 缺血性脑血管疾病, 进展

Abstract:

Ischemic cerebrovascular disease (ICVD) is a disease that seriously endangers human health, and it has the characteristics of acute onset, disability, and high mortality rate. In recent years, the incidence rate has been increasing year by year, and the age of onset is getting younger and younger. Autophagy is a life phenomenon unique to eukaryotes in self-repairing processes, and is a physiological process in which lysosomes in cells degrade phagocytoses. Studies have found that autophagy can be activated after ischemic brain injury, which affects protein expression and internal environment, thereby accelerating or stopping the progression of ICVD. The two-sided nature of autophagy is still unclear, and moderate regulation of autophagy activation may be the key to the protective role of autophagy. This article discusses the related contents of ICVD, autophagy, and the possible protective and damaging effects of autophagy in ICVD, in order to provide new solutions and targets for the diagnosis and treatment of ICVD.

Key words:

Autophagy, Atherosclerosis, Signal path, Ischemic cerebrovascular disease, Progress

蒋萌赵静如刘惠刘庆新.

自噬与缺血性脑血管疾病的研究进展 [J]. 国际医药卫生导报, 2025, 31(8): 1265-1269.

Jiang Meng, Zhao Jingru, Liu Hui, Liu Qingxin.

Research progress on autophagy and ischemic cerebrovascular diseases [J]. International Medicine and Health Guidance News, 2025, 31(8): 1265-1269.

参考文献

[1] Wang XX, Zhang B, Xia R, et al. Inflammation, apoptosis and autophagy as critical players in vascular dementia[J]. Eur Rev Med Pharmacol Sci, 2020,24(18):9601-9614. DOI: 10.26355/eurrev_202009_23048.
[2] Ajoolabady A, Wang S, Kroemer G, et al. Targeting autophagy in ischemic stroke: from molecular mechanisms to clinical therapeutics[J]. Pharmacol Ther, 2021,225:107848. DOI:10.1016/j.pharmthera. 2021.107848
[3] Shi Q, Cheng Q, Chen C. The Role of autophagy in the pathogenesis of ischemic stroke[J]. Curr Neuropharmacol, 2021,19(5):629-640. DOI:10.2174/1570159X18666200729101913
[4] Tu QY, Jin H, Ding BR, et al. Reliability, validity, and optimal cutoff score of the montreal cognitive assessment (Changsha version) in ischemic cerebrovascular disease patients of hunan province, China[J]. Dement Geriatr Cogn Dis Extra, 2013,3(1):25-36. DOI: 10.1159/000346845.
[5] Lugovaya AV, Emanuel VS, Kalinina NM, et al. Apoptosis and autophagy in the pathogenesis of acute ischemic stroke (review of literature)[J]. Klin Lab Diagn, 2020,65(7):428-434. DOI: 10.18821/0869-2084-2020- 65-7-428-434.
[6] 王一茗,束彦页. 自噬在缺血性心脑血管疾病中的作用研究进展[J]. 中国全科医学,2016,19(3):347-351. DOI:10.3969/j.issn.1007-9572.2016.03.023.
[7] Brophy ML, Dong Y, Wu H, et al. Eating the dead to keep atherosclerosis at bay[J]. Front Cardiovasc Med, 2017,4:2. DOI: 10.3389/fcvm.2017.00002.
[8] Evans TD, Jeong SJ, Zhang X, et al. TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis[J]. Autophagy, 2018,14(4):724-726. DOI: 10.1080/15548627.2018.1434373.
[9] Wu X, Zheng Y, Liu M, et al. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains[J]. Autophagy, 2021,17(8):1934-1946. DOI: 10.1080/15548627.2020.1802089.
[10] 王晓平,倪京满.脑缺血再灌注损伤的研究及药物治疗进展[J].中国新药杂志,2016,25(6):659-663,691.
[11] Alishahi M, Farzaneh M, Ghaedrahmati F, et al. NLRP3 inflammasome in ischemic stroke: as possible therapeutic target[J]. Int J Stroke, 2019,14(6):574-591. DOI: 10.1177/1747493019841242.
[12] Jing J, Liu X, Geng X, et al. Autophagy mechanism of cerebral ischemia injury and intervention of traditional Chinese medicine[J]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 2019,31(10):1299-1301. DOI: 10.3760/cma.j.issn.2095-4352.2019.10.024.
[13] 李燕则,郭永清,卫建峰,等. 脑缺血再灌注损伤后自噬机制及自噬相关信号通路的研究进展[J]. 中国当代医药,2018,25(12):29-32. DOI:10.3969/j.issn.1674-4721. 2018.12.008.
[14] 费丰敏,褚欢. 缺血性脑血管病患者外周血细胞自噬因子的表达意义[J]. 中国慢性病预防与控制,2017,25(4):286-289. DOI:10.16386/j.cjpccd.issn.1004-6194.2017.04.014.
[15] Zhu YQ, Xing H, Dai D, et al. Differential interstrain susceptibility to vertebrobasilar dolichoectasia in a mouse model[J]. AJNR Am J Neuroradiol, 2017,38(3):611-616. DOI: 10.3174/ajnr.A5028.
[16] 孙李晴,张智博. 细胞自噬与缺血性脑血管病[J]. 中国实用神经疾病杂志,2015,18(2):137-138. DOI:10.3969/j.issn. 1673-5110.2015.02.091.
[17] Zhang Z, Yang X, Song YQ, et al. Autophagy in Alzheimer's disease pathogenesis: therapeutic potential and future perspectives[J]. Ageing Res Rev, 2021 Dec;72:101464. DOI: 10.1016/j.arr.2021.101464.
[18] Tyutyunyk-Massey L, Gewirtz DA. Roles of autophagy in breast cancer treatment: target, bystander or benefactor[J]. Semin Cancer Biol, 2020,66:155-162. DOI: 10.1016/j.semcancer.2019.11.008.
[19] Choi ME. Autophagy in kidney disease[J]. Annu Rev Physiol, 2020,82:297-322. DOI: 10.1146/annurev- physiol-021119-034658.
[20] 张宁宁,陈永锋,康品方,等. 自噬在肺动脉高压疾病中的作用及研究进展[J]. 淮海医药,2022,40(5):537-540. DOI:10.14126/j.cnki.1008-7044.2022.05.028.
[21] Hu Y, Luo Y, Zheng Y. Nrf2 pathway and autophagy crosstalk: new insights into therapeutic strategies for ischemic cerebral vascular diseases[J]. Antioxidants (Basel), 2022,11(9):1747. DOI: 10.3390/antiox11091747.
[22] Pugsley HR. Assessing autophagic flux by measuring LC3, p62, and LAMP1 co-localization using multispectral imaging flow cytometry[J]. J Vis Exp, 2017(125):55637. DOI: 10.3791/55637.
[23] Ceccariglia S, Cargnoni A, Silini AR, et al. Autophagy: a potential key contributor to the therapeutic action of mesenchymal stem cells[J]. Autophagy, 2020,16(1):28-37. DOI: 10.1080/15548627.2019.1630223.
[24] Du J, Teng RJ, Guan T, et al. Role of autophagy in angiogenesis in aortic endothelial cells[J]. Am J Physiol Cell Physiol, 2012,302(2):C383-391. DOI: 10.1152/ajpcell.00164.2011.
[25] Yao H, Li J, Liu Z, et al. Ablation of endothelial Atg7 inhibits ischemia-induced angiogenesis by upregulating Stat1 that suppresses Hif1a expression[J]. Autophagy, 2023,19(5):1491-1511. DOI: 10.1080/15548627. 2022.2139920.
[26] Liu X, Tian F, Wang S, et al. Astrocyte autophagy flux protects neurons against oxygen-glucose deprivation and ischemic/reperfusion injury[J]. Rejuvenation Res, 2018,21(5):405-415. DOI: 10.1089/rej.2017.1999.
[27] 乔赵娜,黄传江,韩玉亮,等. 细胞自噬在缺血性脑血管病中的作用研究进展[J]. 中国老年学杂志,2013,33(16):4093-4095. DOI:10.3969/j.issn.1005-9202.2013.16.149.
[28] Perez-Alvarez MJ, Villa Gonzalez M, Benito-Cuesta I, et al. Role of mTORC1 controlling proteostasis after brain ischemia[J]. Front Neurosci, 2018,12:60. DOI: 10.3389/fnins.2018.00060.
[29] 付乐. AMPK-mTOR信号通路对自噬的影响在小鼠局灶性脑缺血损伤中的作用[D]. 南昌:南昌大学,2015. DOI:10.7666/d.D692314.
[30] Pei X, Li Y, Zhu L, et al. Astrocyte-derived exosomes suppress autophagy and ameliorate neuronal damage in experimental ischemic stroke[J]. Exp Cell Res, 2019,382(2):111474. DOI: 10.1016/j.yexcr.2019.06.019.
[31] Li J, Liu Z, Wang L, et al. Thousand and one kinase 1 protects MCAO-induced cerebral ischemic stroke in rats by decreasing apoptosis and pro-inflammatory factors[J]. Biosci Rep, 2019,39(10):BSR20190749. DOI: 10.1042/BSR20190749.
[32] Norrving B, Kissela B. The global burden of stroke and need for a continuum of care[J]. Neurology, 2013,80(3 Suppl 2):S5-12. DOI: 10.1212/WNL.0b013e3182762397.
[33] Zhang Q, Yao M, Qi J, et al. Puerarin inhibited oxidative stress and alleviated cerebral ischemia-reperfusion injury through PI3K/Akt/Nrf2 signaling pathway[J]. Front Pharmacol, 2023,14:1134380. DOI: 10.3389/fphar.2023.1134380.
[34] Qiao W, Zang Z, Li D, et al. Liensinine ameliorates ischemia-reperfusion-induced brain injury by inhibiting autophagy via PI3K/AKT signaling[J]. Funct Integr Genomics, 2023,23(2):140. DOI: 10.1007/s10142-023-01063-7.
[35] Chen DP, Hou SH, Chen YG, et al. L-butyl phthalein improves neural function of vascular dementia mice by regulating the PI3K/AKT signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2018,22(16):5377-5384. DOI: 10.26355/eurrev_201808_15740.
[36] Lee KM, Bang J, Kim BY, et al. Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling[J]. BMC Complement Altern Med, 2015,15:125. DOI: 10.1186/s12906-015-0652-1.
[37] Yang S, Wang H, Yang Y, et al. Baicalein administered in the subacute phase ameliorates ischemia-reperfusion-induced brain injury by reducing neuroinflammation and neuronal damage[J]. Biomed Pharmacother, 2019,117:109102. DOI: 10.1016/j.biopha.2019.109102.
[38] Roy Choudhury G, Ryou MG, Poteet E, et al. Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke[J]. Brain Res, 2014,1551:45-58. DOI: 10.1016/j.brainres.2014.01.013.
[39] Wang PR, Wang JS, Zhang C, et al. Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway[J]. J Ethnopharmacol, 2013,149(1):270-280. DOI: 10.1016/j.jep.2013.06.035.
[40] Yang H, Li L, Zhou K, et al. Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways[J]. Pharm Biol, 2016,54(10):2288-2297. DOI: 10.3109/13880209.2016.1155625.
[41] 徐继伟. 依达拉奉对SAH大鼠海马区JNK-自噬信号通路的影响[D].唐山:华北理工大学,2016. DOI:10.7666/d.D01086048.
[42] Zhao Y, Shi X, Wang J, et al. Betulinic acid ameliorates cerebral injury in middle cerebral artery occlusion rats through regulating autophagy[J]. ACS Chem Neurosci, 2021,12(15):2829-2837. DOI: 10.1021/acschemneuro.1c00198.
[43] Mei ZG, Huang YG, Feng ZT, et al. Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway[J]. Aging (Albany NY), 2020,12(13):13187-13205. DOI: 10.18632/aging.103420.
[44] 齐玉彦,张淑岩,沈鹏,等. 胱抑素C与缺血性脑血管病的研究进展[J]. 卒中与神经疾病,2018,25(3):329-331. DOI:10.3969/j.issn.1007-0478.2018.03.025.
[45] Yang Z, Lin P, Chen B, et al. Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5)[J]. Autophagy, 2021,17(10):3048-3067. DOI: 10.1080/15548627.2020.1851897.
[46] Xu S, Huang P, Yang J, et al. Calycosin alleviates cerebral ischemia/reperfusion injury by repressing autophagy via STAT3/FOXO3a signaling pathway[J]. Phytomedicine, 2023,115:154845. DOI: 10.1016/j.phymed.2023.154845.
[47] Shen L, Gan Q, Yang Y, et al. Mitophagy in cerebral ischemia and ischemia/reperfusion injury[J]. Front Aging Neurosci, 2021,13:687246. DOI: 10.3389/fnagi. 2021.687246.