Please wait a minute...
J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (3): 390-395    DOI: 10.3724/zdxbyxb-2021-0190
Research advance of Nrf2 on atherosclerosis by regulating vascular smooth muscle cell
ZHUANG Wenwen1(),YANG Yongqi1,LI Hongliang1,2,LIANG Jingyan1,2,*()
1. Medical College, Yangzhou University, Yangzhou 225000, Jiangsu Province, China;
2. Institute of Translational Medicine, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
Download: HTML( 18 )   PDF(2017KB)
Export: BibTeX | EndNote (RIS)      


Atherosclerosis is a common pathological change in cardiovascular disease. Vascular smooth muscle cell is the main source of plaque cell and extracellular matrix, and nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the function of vascular smooth muscle cell. In the process of atherosclerosis, Nrf2 signaling pathway has the following regulatory effects on vascular smooth muscle cell: regulating the phenotype of vascular smooth muscle cell to change to the direction conducive to the alleviation of disease progression; inhibiting the proliferation and migration of vascular smooth muscle cell; mitigating the level of blood lipid; alleviating vascular smooth muscle cell calcification, aging and apoptosis process. This article reviews the specific mechanisms of Nrf2 regulating atherosclerosis, such as phenotypic transformation, proliferation and migration, lipid metabolism, calcification, aging and apoptosis in atherosclerosis, in order to provide a basis for understanding the molecular mechanism of atherosclerosis development and finding therapeutic targets.

Key wordsAtherosclerosis      Vascular smooth muscle cell      Nuclear factor-erythroid 2- related factor 2      Review     
Received: 20 December 2020      Published: 16 August 2021
CLC:  R543.5  
Corresponding Authors: LIANG Jingyan     E-mail:;
Cite this article:

ZHUANG Wenwen,YANG Yongqi,LI Hongliang,LIANG Jingyan. Research advance of Nrf2 on atherosclerosis by regulating vascular smooth muscle cell. J Zhejiang Univ (Med Sci), 2021, 50(3): 390-395.

URL:     OR



关键词: 动脉粥样硬化,  血管平滑肌细胞,  核因子E2相关因子2,  综述 
[1]   FRISMANTIENEA, PHILIPPOVAM, ERNEP, et al.Smooth muscle cell-driven vascular diseases and molecular mechanisms of VSMC plasticity[J]Cell Signal, 2018, 48-64.
doi: 10.1016/j.cellsig.2018.08.019
[2]   YOSHIDAT, YAMASHITAM, HORIMAIC, et al.Smooth muscle-selective inhibition of nuclear factor‐κb attenuates smooth muscle phenotypic switching and neointima formation following vascular injury[J]J Am Heart Assoc, 2013, 2( 3): 230.
doi: 10.1161/JAHA.113.000230
[3]   NAVAS-MADRO?ALM, CASTELBLANCOE, CAMACHOM, et al.Role of the scavenger receptor cd36 in accelerated diabetic atherosclerosis[J]Int J Mol Sci, 2020, 21( 19): 7360.
doi: 10.3390/ijms21197360
[4]   KATTOORA J, POTHINENIN V K, PALAGIRID, et al.Oxidative stress in atherosclerosis[J]Curr Atheroscler Rep, 2017, 19( 11): 42.
doi: 10.1007/s11883-017-0678-6
[5]   MAGUIREE M, XIAOQ. Noncoding RNAs in vascular smooth muscle cell function and neointimal hyperplasia[J]FEBS J, 2020, 287( 24): 5260-5283.
doi: 10.1111/febs.15357
[6]   POZNYAKA V, GRECHKOA V, OREKHOVAV A, et al.Oxidative stress and antioxidants in atherosclerosis development and treatment[J]Biology, 2020, 9( 3): 60.
doi: 10.3390/biology9030060
[7]   WOLFM P, HUNZIKERP. Atherosclerosis: insights into vascular pathobiology and outlook to novel treatments[J]J Cardiovasc Trans Res, 2020, 13( 5): 744-757.
doi: 10.1007/s12265-020-09961-y
[8]   DORANA C, MELLERN, MCNAMARAC A. Role of smooth muscle cells in the initiation and early progression of atherosclerosis[J]Arterioscler Thromb Vasc Biol, 2008, 28( 5): 812-819.
doi: 10.1161/ATVBAHA.107.159327
[9]   CHIND D, POONC, WANGJ, et al.miR-145 micelles mitigate atherosclerosis by modulating vascular smooth muscle cell phenotype[J/OL]Biomaterials, 2021, 120810.
doi: 10.1016/j.biomaterials.2021.120810
[10]   SEONGM, KANGH. Hypoxia-induced miR-1260b regulates vascular smooth muscle cell proliferation by targeting GDF11[J]BMB Rep, 2020, 53( 4): 206-211.
doi: 10.5483/BMBREP.2020.53.4.136
[11]   KUOSMANENS M, VIITALAS, LAITINENT, et al.The effects of sequence variation on genome-wide nrf2 binding—new target genes and regulatory snps[J]Nucleic Acids Res, 2016, 44( 4): 1760-1775.
doi: 10.1093/nar/gkw052
[12]   DA COSTAR M, RODRIGUESD, PEREIRAC A, et al.Nrf2 as a potential mediator of cardiovascular risk in metabolic diseases[J]Front Pharmacol, 2019, 382.
doi: 10.3389/fphar.2019.00382
[13]   UNGVARIZ, TARANTINIS, NYúL-TóTHá, et al.Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases[J]GeroScience, 2019, 41( 6): 727-738.
doi: 10.1007/s11357-019-00107-w
[14]   CAIH, LIUY, MENH, et al.Protective mechanism of humanin against oxidative stress in aging-related cardiovascular diseases[J]Front Endocrinol, 2021, 68315.
doi: 10.3389/fendo.2021.683151
[15]   FREIGANGS, AMPENBERGERF, SPOHNG, et al.Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis[J]Eur J Immunol, 2011, 41( 7): 2040-2051.
doi: 10.1002/eji.201041316
[16]   NIEDZIELSKIM, BRONCELM, GORZELAK-PABI?P, et al.New possible pharmacological targets for statins and ezetimibe[J]Biomed PharmacoTher, 2020, 110388.
doi: 10.1016/j.biopha.2020.110388
[17]   PANH, XUEC, AUERBACHB J, et al.Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human[J]Circulation, 2020, 142( 21): 2060-2075.
doi: 10.1161/circulationaha.120.048378
[18]   BENTZONJ F, MAJESKYM W. Lineage tracking of origin and fate of smooth muscle cells in atherosclerosis[J]Cardiovascular Res, 2018, 114( 4): 492-500.
doi: 10.1093/cvr/cvx251
[19]   HEX, DENGJ, YUX J, et al.Activation of m3achr (type 3 muscarinic acetylcholine receptor) and Nrf2 (nuclear factor erythroid 2-related factor 2) signaling by choline alleviates vascular smooth muscle cell phenotypic switching and vascular remodeling[J]Arterioscler Thromb Vasc Biol, 2020, 40( 11): 2649-2664.
doi: 10.1161/ATVBAHA.120.315146
[20]   BUGLAKN E, JIANGW, BAHNSONE S M. Cinnamic aldehyde inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in Zucker diabetic fatty rats[J]Redox Biol, 2018, 166-178.
doi: 10.1016/j.redox.2018.08.013
[21]   ASHINOT, YAMAMOTOM, YOSHIDAT, et al.Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia[J]Arterioscler Thromb Vasc Biol, 2013, 33( 4): 760-768.
doi: 10.1161/ATVBAHA.112.300614
[22]   HWANGA R, HANJ H, LIMJ H, et al.Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells[J/OL]PLoS One, 2017, 12( 5): e0178278.
doi: 10.1371/journal.pone.0178278
[23]   KOW C, SHIEHJ M, WUW B. P38 mapk and nrf2 activation mediated naked gold nanoparticle induced heme oxygenase-1 expression in rat aortic vascular smooth muscle cells[J]Archives Med Res, 2020, 51( 5): 388-396.
doi: 10.1016/j.arcmed.2020.04.015
[24]   SHAWKYN M, SEGARL. Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation[J]Pharmacological Res, 2017, 251-264.
doi: 10.1016/j.phrs.2017.02.010
[25]   HWANGS M, LEEY J, LEEY P, et al.Anti-proliferative effect of an aqueous extract of Prunella vulgaris in vascular smooth muscle cells[J]Evid Based Complement Alternat Med, 2013, 936463.
doi: 10.1155/2013/936463
[26]   SEOY, PARKJ, CHOIW, et al.Antiatherogenic effect of resveratrol attributed to decreased expression of icam-1 (intercellular adhesion molecule-1)[J]Arterioscler Thromb Vasc Biol, 2019, 39( 4): 675-684.
doi: 10.1161/ATVBAHA.118.312201
[27]   YUEH, FEBBRAIOM, KLENOTICP A, et al.Cd36 enhances vascular smooth muscle cell proliferation and development of neointimal hyperplasia[J]Arterioscler Thromb Vasc Biol, 2019, 39( 2): 263-275.
doi: 10.1161/ATVBAHA.118.312186
[28]   DURHAMA L, SPEERM Y, SCATENAM, et al.Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness[J]Cardiovasc Res, 2018, 114( 4): 590-600.
doi: 10.1093/cvr/cvy010
[29]   WEIR, ENAKAM, MURAGAKIY. Activation of KEAP1/NRF2/P62 signaling alleviates high phosphate-induced calcification of vascular smooth muscle cells by suppressing reactive oxygen species production[J]Sci Rep, 2019, 9( 1): 10366.
doi: 10.1038/s41598-019-46824-2
[30]   OKSANENM, HY?TYL?INENI, TRONTTIK, et al.NF‐E2‐related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin‐1 mutated Alzheimer’s disease astrocytes[J]Glia, 2020, 68( 3): 589-599.
doi: 10.1002/glia.23741
[31]   CUADRADOA, ROJOA I, WELLSG, et al.Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases[J]Nat Rev Drug Discov, 2019, 18( 4): 295-317.
doi: 10.1038/s41573-018-0008-x
[32]   CUADRADOA, MANDAG, HASSANA, et al.Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach[J]Pharmacol Rev, 2018, 70( 2): 348-383.
doi: 10.1124/pr.117.014753
[33]   PANIERIE, SASOL. Potential applications of NRF2 inhibitors in cancer therapy[J]Oxid Med Cell Longev, 2019, 8592348.
doi: 10.1155/2019/8592348
[34]   XUT H, DUY, SHENGZ, et al.OGT-mediated keap1 glycosylation accelerates Nrf2 degradation leading to high phosphate-induced vascular calcification in chronic kidney disease[J]Front Physiol, 2020, 1092.
doi: 10.3389/fphys.2020.01092
[35]   PENNINGTONS M, KLUTHOP R, XIEL, et al.Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription[J]Redox Biol, 2018, 401-413.
doi: 10.1016/j.redox.2018.04.001
[36]   AGHAGOLZADEHP, RADPOURR, BACHTLERM, et al.Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/NRF2/NQO1 activation[J]Atherosclerosis, 2017, 78-86.
doi: 10.1016/j.atherosclerosis.2017.08.012
[37]   GIANNOTTIK C, WEINERTS, VIANAM N, et al.A secreted phospholipase A2 induces formation of smooth muscle foam cells which transdifferentiate to macrophage-like state[J]Molecules, 2019, 24( 18): 3244.
doi: 10.3390/molecules24183244
[38]   HEL H, GAOJ H, YUX H, et al.Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway[J]Eur J Pharmacol, 2020, 173408.
doi: 10.1016/j.ejphar.2020.173408
[39]   MALTESEG, PSEFTELIP M, RIZZOB, et al.The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells[J]J Cell Mol Med, 2017, 21( 3): 621-627.
doi: 10.1111/jcmm.12996
[1] HU Jingyi,WANG Qingqing,LIU Yang. Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma[J]. J Zhejiang Univ (Med Sci), 2021, 50(3): 396-402.
[2] GE Yingzhou,LIU Xinmei,HUANG Hefeng. Advances in the role of silence information regulator family in pathological pregnancy[J]. J Zhejiang Univ (Med Sci), 2021, 50(3): 335-344.
[3] WANG Jintao,HUANG Lei,WEI Lili,CHEN Wei. Factors affecting the efficacy of repetitive transcranial magnetic stimulation for patients with Alzheimer’s disease[J]. J Zhejiang Univ (Med Sci), 2021, 50(3): 383-389.
[4] KUANG Wenjing,LUO Xiaobo,WANG Jiongke,ZENG Xin. Research progress on Melkersson-Rosenthal syndrome[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 148-154.
[5] WANG Chenyu,WANG Yingnan,WANG Cunyi,SHI Jiejun,WANG Huiming. Research progress on tissue engineering in repairing temporo-mandibular joint[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 212-221.
[6] REN Chaojie,ZHONG Danni,ZHOU Min. Research progress on the biomedical application of microalgae[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 261-266.
[7] YING Yingchao,JIANG Peifang. Research progress on transient receptor potential melastatin 2 channel in nervous system diseases[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 267-276.
[8] SHAO Yiming,SU Lide,HAO Rui,WANG Qianqian,NARANMANDURA Hua. Advances on molecular mechanism of hepatitis B virus-induced hepatocellular carcinoma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 113-122.
[9] HAN Hengyi,FENG Fan,LI Haitao. Research advances on epigenetics and cancer metabolism[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 1-16.
[10] CHEN Fei,YU Min,ZHONG Yonghong,HUA Wen,HUANG Huaqiong. The role of neutrophils in asthma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 123-130.
[11] YAN Jing,ZHANG Tingting,ZHAO Kui. Application of molecular probes in nuclear imaging of neuroendocrine tumors[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 131-137.
[12] ZHANG Mingquan,PAN Junchen,HUANG Peng. Interaction between RAS gene and lipid metabolism in cancer[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 17-22.
[13] HU Xinyang,JIN Hongchuan,ZHU Liyuan. Effect of glutamine metabolism on chemoresistance and its mechanism in tumors[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 32-40.
[14] MENG Ying,WANG Qifei,LYU Zhimin. Cholesterol metabolism and tumor[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 23-31.
[15] ZHU Huiqi,YING Kejing. Tissue factors and venous thromboembolism in cancer patients[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 772-778.