Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2022, Vol. 51 Issue (1): 95-101    DOI: 10.3724/zdxbyxb-2021-0270
综述     
细胞衰老与动脉粥样硬化的相关研究进展
刘德坤1,刘佳丽1,张丹2,*(),杨雯晴3,*()
1.山东中医药大学中医学院，山东 济南 250300
2.山东中医药大学实验中心，山东 济南 250300
3.山东中医药大学创新研究院，山东 济南 250300
Advances in relationship between cell senescence and atherosclerosis
LIU Dekun1,LIU Jiali1,ZHANG Dan2,*(),YANG Wenqing3,*()
1. Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250300, China;
2. Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250300, China;
3. Innovation Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250300, China
 全文: PDF(2025 KB)   HTML( 27 )
摘要：

细胞衰老是一种与细胞结构和功能退化相关的生物过程，与年龄相关的疾病有着复杂的联系。动脉粥样硬化是一种慢性炎症性疾病，可引起多种心血管疾病。本文就细胞衰老过程中，多种衰老细胞产生不同的生理病理变化对动脉粥样硬化的影响，衰老细胞器的改变和衰老细胞分泌的衰老相关分泌表型（SASP）的增多促进动脉粥样硬化的进展，以及针对清除衰老细胞和减少SASP以减轻动脉粥样硬化的相关治疗方法等研究进展进行综述，以期为动脉粥样硬化的治疗提供新的思路。
关键词： 动脉粥样硬化;  衰老细胞;  细胞器;  衰老相关分泌表型;  治疗策略;  综述    
Abstract:

Cellular senescence is a biological process associated with the degeneration of cell structure and function, which contribute to age-related diseases. Atherosclerosis is a chronic inflammatory disease that can cause a variety of cardiovascular disorders. In this article, we review the effects of cellular senescence on the development of atherosclerosis through diverse physiopathological changes, focusing on the alterations in senescent organelles and the increased senescence-associated secretory phenotype (SASP), and exploring the relevant therapeutic strategies for atherosclerosis by clearing senescent cells and reducing SASP, to provide new insights for the treatment of atherosclerosis.
Key words: Atherosclerosis    Senescence cells    Organelles    Senescence-associated secretory phenotype    Treatment strategies    Review
收稿日期: 2021-09-03 出版日期: 2022-05-17
CLC:  R543.5  
基金资助: 国家自然科学基金（81804006，82174337）；山东省医药卫生科技发展计划（2019WS556，2019WS553）
通讯作者: 张丹,杨雯晴     E-mail: winnie0416q@163.com
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
刘德坤
刘佳丽
张丹
杨雯晴

引用本文:

刘德坤,刘佳丽,张丹,杨雯晴. 细胞衰老与动脉粥样硬化的相关研究进展[J]. 浙江大学学报（医学版）, 2022, 51(1): 95-101.

LIU Dekun,LIU Jiali,ZHANG Dan,YANG Wenqing. Advances in relationship between cell senescence and atherosclerosis. J Zhejiang Univ (Med Sci), 2022, 51(1): 95-101.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0270    或    https://www.zjujournals.com/med/CN/Y2022/V51/I1/95

细胞器

功能改变

影响

线粒体

线粒体功能障碍相关衰老；线粒体DNA损伤；活性氧增加

血管老化、顺应性降低；炎症因子增加；脂质沉积

溶酶体

溶酶体酸碱度改变

细胞自噬能力降低；脂质沉积增加

细胞核

核稳定性降低

DNA损伤增加

内质网

未折叠蛋白质反应激活

刺激核因子κB；炎症因子增加；细胞形态改变
表 1  衰老对细胞器功能的影响
1 BENNETTM R, SINHAS, OWENSG K. Vascular smooth muscle cells in atherosclerosis[J]Circ Res, 2016, 118( 4): 692-702.
doi: 10.1161/CIRCRESAHA.115.306361
2 FYHRQUISTF, SAIJONMAAO, STRANDBERGT. The roles of senescence and telomere shortening in cardiovascular disease[J]Nat Rev Cardiol, 2013, 10( 5): 274-283.
doi: 10.1038/nrcardio.2013.30
3 VAN DEURSENJ M. The role of senescent cells in ageing[J]Nature, 2014, 509( 7501): 439-446.
doi: 10.1038/nature13193
4 LUSISA J. Atherosclerosis[J]Nature, 2000, 407( 6801): 233-241.
doi: 10.1038/35025203
5 SABBATINELLIJ, VIGNINIA, SALVOLINIE, et al.Platelet-derived NO in subjects affected by type 2 diabetes with and without complications: is there any relationship with their offspring?[J]Exp Clin Endocrinol Diabetes, 2017, 125( 5): 290-296.
doi: 10.1055/s-0043-102578
6 PALOTN B, SIMONCINIS, ROBERTS, et al.Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment[J]Atherosclerosis, 2014, 237( 1): 45-52.
doi: 10.1016/j.atherosclerosis.2014.08.036
7 HUANGP L, HUANGZ, MASHIMOH, et al.Hypertension in mice lacking the gene for endothelial nitric oxide synthase[J]Nature, 1995, 377( 6546): 239-242.
doi: 10.1038/377239a0
8 SATOI, MORITAI, KAJIK, et al.Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell[J]Biochem Biophysl Res Commun, 1993, 195( 2): 1070-1076.
doi: 10.1006/bbrc.1993.2153
9 DONATOA J, GANOL B, ESKURZAI, et al.Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase[J]Am J Physiol Heart Circ Physiol, 2009, 297( 1): H425-H432.
doi: 10.1152/ajpheart.00689.2008
10 CHIENY, SCUOPPOC, WANGX, et al.Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity[J]Genes Dev, 2011, 25( 20): 2125-2136.
doi: 10.1101/gad.17276711
11 HASEGAWAY, SAITOT, OGIHARAT, et al.Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans[J]Circulation, 2012, 125( 9): 1122-1133.
doi: 10.1161/CIRCULATIONAHA.111.054346
12 ALIQUEM, RUÍZ-TORRESM P, BODEGAG, et al.Microvesicles from the plasma of elderly subjects and from senescent endothelial cells promote vascular calcification[J]Aging, 2017, 9( 3): 778-789.
doi: 10.18632/aging.101191
13 GARDNERS E, HUMPHRYM, BENNETTM R, et al.Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype[J]Arterioscler Thromb Vasc Biol, 2015, 35( 9): 1963-1974.
doi: 10.1161/ATVBAHA.115.305896
14 MINAMINOT, YOSHIDAT, TATENOK, et al.Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis[J]Circulation, 2003, 108( 18): 2264-2269.
doi: 10.1161/01.CIR.0000093274.82929.22
15 JOHNSONR C, LEOPOLDJ A, LOSCALZOJ. Vascular calcification[J]Circ Res, 2006, 99( 10): 1044-1059.
doi: 10.1161/01.RES.0000249379.55535.21
16 LEEJ, YOONS R, CHOII, et al.Causes and mechanisms of hematopoietic stem cell aging[J]Int J Mol Sci, 2019, 20( 6): 1272.
doi: 10.3390/ijms20061272
17 NAKAJIMAT, SCHULTES, WARRINGTONK J, et al.T-cell-mediated lysis of endothelial cells in acute coronary syndromes[J]Circulation, 2002, 105( 5): 570-575.
doi: 10.1161/hc0502.103348
18 VENTURAM T, CASCIAROM, GANGEMIS, et al.Immunosenescence in aging: between immune cells depletion and cytokines up-regulation[J]Clin Mol Allergy, 2017, 15( 1): 21.
doi: 10.1186/s12948-017-0077-0
19 TYRRELLD J, GOLDSTEIND R. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6[J]Nat Rev Cardiol, 2021, 18( 1): 58-68.
doi: 10.1038/s41569-020-0431-7
20 CALVERTP A, LIEWT V, GORENNEI, et al.Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity[J]Arterioscler Thromb Vasc Biol, 2011, 31( 9): 2157-2164.
doi: 10.1161/ATVBAHA.111.229237
21 KIRKLANDJ L, TCHKONIAT. Cellular senescence: a translational perspective[J]EBioMedicine, 2017, 21-28.
doi: 10.1016/j.ebiom.2017.04.013
22 ZHUY, TCHKONIAT, PIRTSKHALAVAT, et al.The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs[J]Aging Cell, 2015, 14( 4): 644-658.
doi: 10.1111/acel.12344
23 ROOSC M, ZHANGB, PALMERA K, et al.Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice[J]Aging Cell, 2016, 15( 5): 973-977.
doi: 10.1111/acel.12458
24 FANGJ, LITTLEP J, XUS. Atheroprotective effects and molecular targets of tanshinones derived from herbal medicine danshen[J]Med Res Rev, 2018, 38( 1): 201-228.
doi: 10.1002/med.21438
25 OLIVEIRAG M, RAMOSC, MARQUESA R A, et al.Cell senescence, multiple organelle dysfunction and atherosclerosis[J]Cells, 2020, 9( 10): 2146.
doi: 10.3390/cells9102146
26 LÓPEZ-OTÍNC, BLASCOM A, PARTRIDGEL, et al.The hallmarks of aging[J]Cell, 2013, 153( 6): 1194-1217.
doi: 10.1016/j.cell.2013.05.039
27 WEIW, JIS. Cellular senescence: molecular mechanisms and pathogenicity[J]J Cell Physiol, 2018, 233( 12): 9121-9135.
doi: 10.1002/jcp.26956
28 FOOTEK, REINHOLDJ, YUE P K, et al.Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice[J/OL]Aging Cell, 2018, 17( 4): e12773.
doi: 10.1111/acel.12773
29 YUE, CALVERTP A, MERCERJ R, et al.Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans[J]Circulation, 2013, 128( 7): 702-712.
doi: 10.1161/CIRCULATIONAHA.113.002271
30 OGRODNIKM, MIWAS, TCHKONIAT, et al.Cellular senescence drives age-dependent hepatic steatosis[J]Nat Commun, 2017, 8( 1): 15691.
doi: 10.1038/ncomms15691
31 LIUJ, LUW, REIGADAD, et al.Restoration of lysosomal pH in RPE cells from cultured human and ABCA4−/− mice: pharmacologic approaches and functional recovery[J]Invest Ophthalmol Vis Sci, 2008, 49( 2): 772.
doi: 10.1167/iovs.07-0675
32 SCHNEIDERJ L, CUERVOA M. Autophagy and human disease: emerging themes[J]Curr Opin Genet Dev, 2014, 16-23.
doi: 10.1016/j.gde.2014.04.003
33 AHMADF, LEAKED S. Lysosomal oxidation of LDL alters lysosomal pH, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages[J]J Lipid Res, 2019, 60( 1): 98-110.
doi: 10.1194/jlr.M088245
34 NARITAM, NUÑEZS, HEARDE, et al.Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence[J]Cell, 2003, 113( 6): 703-716.
doi: 10.1016/S0092-8674(03)00401-X
35 ZHANGR, POUSTOVOITOVM V, YEX, et al.Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA[J]Dev Cell, 2005, 8( 1): 19-30.
doi: 10.1016/j.devcel.2004.10.019
36 PLUQUETO, POURTIERA, ABBADIEC. The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease[J]Am J Physiol Cell Physiol, 2015, 308( 6): C415-C425.
doi: 10.1152/ajpcell.00334.2014
37 CIVELEKM, MANDUCHIE, RILEYR J, et al.Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis[J]Circ Res, 2009, 105( 5): 453-461.
doi: 10.1161/CIRCRESAHA.109.203711
38 MATOSL, GOUVEIAA M, ALMEIDAH. ER stress response in human cellular models of senescence[J]J Gerontol A Biol Sci Med Sci, 2015, 70( 8): 924-935.
doi: 10.1093/gerona/glu129
39 CHENX, GUOX, GEQ, et al.ER stress activates the NLRP3 inflammasome: a novel mechanism of atherosclerosis[J]Oxid Med Cell Longev, 2019, 1-18.
doi: 10.1155/2019/3462530
40 TAMA B, MERCADOE L, HOFFMANNA, et al.ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK[J/OL]PLoS One, 2012, 7( 10): e45078.
doi: 10.1371/journal.pone.0045078
41 FRANCESCO P, VALERIA D N, LUCIA L S, et al. “Inflammaging” as a druggable target: a senescence-associated secretory phenotype——centered view of type 2 diabetes[J]. Oxidative medicine and cellular longevity, 2016, (5): 1-10
42 ACOSTAJ C, O'LOGHLENA, BANITOA, et al.Chemokine signaling via the CXCR2 receptor reinforces senescence[J]Cell, 2008, 133( 6): 1006-1018.
doi: 10.1016/j.cell.2008.03.038
43 KUILMANT, MICHALOGLOUC, VREDEVELDL C W, et al.Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network[J]Cell, 2008, 133( 6): 1019-1031.
doi: 10.1016/j.cell.2008.03.039
44 ROSE-JOHNS, WINTHROPK, CALABRESEL. The role of IL-6 in host defence against infections: immunobiology and clinical implications[J]Nat Rev Rheumatol, 2017, 13( 7): 399-409.
doi: 10.1038/nrrheum.2017.83
45 SCHUETTH, OESTREICHR, WAETZIGG H, et al.Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice[J]Arterioscler Thromb Vasc Biol, 2012, 32( 2): 281-290.
doi: 10.1161/ATVBAHA.111.229435
46 WALTERSH E, DENEKA-HANNEMANNS, COXL S. Reversal of phenotypes of cellular senescence by pan-mTOR inhibition[J]Aging, 2016, 8( 2): 231-244.
doi: 10.18632/aging.100872
47 BENNACEURK, ATWILLM, AL ZHRANYN, et al.Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism[J]Atherosclerosis, 2014, 236( 2): 312-320.
doi: 10.1016/j.atherosclerosis.2014.07.020
48 MAHMOUDIM, GORENNEI, MERCERJ, et al.Statins use a novel nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells[J]Circ Res, 2008, 103( 7): 717-725.
doi: 10.1161/CIRCRESAHA.108.182899
[1] 汪文妮,陈超群,顾新华. 磁性纳米粒子复合支架及外加磁场影响成骨作用的研究进展[J]. 浙江大学学报（医学版）, 2022, 51(1): 102-107.
[2] 边梦瑶,陈莉丽,雷利红. 慢性牙周炎与帕金森病相关性的研究进展[J]. 浙江大学学报（医学版）, 2022, 51(1): 108-114.
[3] 金群,黄丽华. 神经认知障碍患者多成分运动干预的研究进展[J]. 浙江大学学报（医学版）, 2022, 51(1): 38-46.
[4] 卢茜璇,包黎莎,潘宗富,葛明华. 甲状腺未分化癌免疫治疗的现状及未来[J]. 浙江大学学报（医学版）, 2021, 50(6): 675-684.
[5] 钱晨宏,蒋烈浩,许世莹,王佳峰,谭卓,忻莹,葛明华. 甲状腺未分化癌靶向治疗研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 685-693.
[6] 周靖,王艳,徐恩萍. 微单倍型在法医遗传学中的研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 777-782.
[7] 任渊,崔戈丹,高永翔. 原发性干燥综合征患者颌下腺炎症反应机制研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 783-794.
[8] 马丽娟,吴爽,张凯,田梅,张宏. 大麻素1型受体正电子发射断层显像在神经精神疾病中的应用进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 666-673.
[9] 宣自学,张轶雯,潘宗富,郑小卫,黄萍. 天然药物成分干预铁死亡抑制肿瘤的作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 601-606.
[10] 曲文政,庄英粮,李学坤. 表观遗传修饰在神经退行性变性疾病中的作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 642-650.
[11] 孙琦,曹蔚,罗建红. 含GluN3亚基的N-甲基-D-天冬氨酸受体及其在中枢神经系统的功能[J]. 浙江大学学报（医学版）, 2021, 50(5): 651-658.
[12] 史建蓉,马望前,汤慧芳. 磷酸二酯酶抑制剂治疗炎性肠病的研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 659-665.
[13] 唐玥,孔元原. 遗传性酪氨酸血症Ⅰ型及其筛查和诊治进展[J]. 浙江大学学报（医学版）, 2021, 50(4): 514-523.
[14] 刘飞,冯春月,毛建华,傅海东. 2019冠状病毒病疫苗接种相关新发及复发肾小球病研究进展[J]. 浙江大学学报（医学版）, 2021, 50(4): 524-528.
[15] 韩连书. 新生儿遗传病基因筛查技术及相关疾病[J]. 浙江大学学报（医学版）, 2021, 50(4): 429-435.