Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress

J Adv Res. 2021 Jul 6:34:43-63. doi: 10.1016/j.jare.2021.06.023. eCollection 2021 Dec.


Introduction: Recently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury.

Objectives: This paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs.

Methods: A literature search was carried out regarding our topic with the keywords of "atherosclerosis" or "Nrf2/HO-1" or "vascular endothelial cells" or "oxidative stress" or "Herbal medicine" or "natural products" or "natural extracts" or "natural compounds" or "traditional Chinese medicines" based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed.

Results: These agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies.

Conclusion: Our present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Keywords: 7-HMR, (−)-7(S)-hydroxymatairesinol; ADH, andrographolide; AGE, advanced glycation end product; AMP, Athyrium Multidentatum; APV, aqueous extracts of Prunella Vulgaris; ARE, antioxidant reaction elements; AS, atherosclerosis; ASD-IV, Astragaloside IV; ASP, Angelica sinensis polysaccharide; ASTP, Astragalus polysacharin; Akt, protein kinase B; Ang, Angiotensin; ApoE, apolipoprotein E; Atherosclerosis; BAECs, bovine artery endothelial cells; BBR, Berberine; BITC, benzyl isothiocyanate; C3G, Cyanidin-3-O-glucoside; CINM, Cinnamaldehyde; CNC, Cap'n'collar; CREB, cAMP-response element binding protein; CVDs, cardiovascular diseases; CVRF, cardiovascular risk factors; DMY, Dihydromyricetin; ECC, (−)-Epicatechin; ECs, endothelial cells; EGCG, epigallocatechin-3-O-gallate; ERK, extracellular regulated protein kinases; ET, endothelin; EXS, Xanthoceras sorbifolia; FFA, Fatty Acids; GPx, Glutathione peroxidase; GSD Rg1, Ginsenoside Rg1; GTE, Ganoderma tsugae extracts; Gau A, Glaucocalyxin A; HAMS, human anthocyanin medicated serum; HG, high glucose; HIF-1, Hypoxia-inducible factor 1; HO-1, heme oxygenase; HUVECs, human umbilical vein endothelial cells; HXC, Huoxue capsule; Hcy, Homocysteine; Herbal medicine; ICAM, intercellular adhesion molecule; IL, interleukin; KGRE, extracts of KGR; KRG, Korean red ginseng; Keap1, kelch-like epichlorohydrin-related proteins; LWDH, Liuwei-Dihuang pill; MA, maslinic acid; MAPKK, mitogen-activated protein kinase kinase; MAPKs, mitogen-activated protein kinases; MCGA3, 3-O-caffeoyl-1-methylquinic acid; MCP-1, monocyte chemotactic protein 1; MMPs, matrix metalloproteinases; Molecular mechanism; NAF, Nepeta Angustifolia; NF-κB, nuclear factor kappa-B; NG, naringenin; NQO1, NAD(P)H: quinone oxidoreductase; Nrf2, nuclear factor erythroid-2 related factor 2; Nrf2/HO-1 signaling; OA, Oleanolic acid; OMT, Oxymatrine; OX-LDL, oxidized low density lipoprotein; Oxidative stress; PA, Palmitate; PAA, Pachymic acid; PAI-1, plasminogen activator Inhibitor-1; PEITC, phenethyl isocyanate; PI3K, phosphatidylinositol 3 kinase; PKC, protein kinase C; PT, Pterostilbene; RBPC, phenolic extracts derived from rice bran; ROS, reactive oxygen species; SAL, Salidroside; SFN, sulforaphane; SMT, Samul-Tang Tang; SOD, superoxide dismutase; Sal B, salvianolic acid B; SchB, Schisandrin B; TCM, traditional Chinese medicine; TNF, tumor necrosis factor; TXA2, Thromboxane A2; TrxR1, thioredoxin reductase-1; US, uraemic serum; VA, Vanillic acid; VCAM, vascular cell adhesion molecule; VEC, vascular endothelial cells; VEI, vascular endothelial injury; Vascular endothelial cells; XAG, xanthoangelol; XXT, Xueshuan Xinmaining Tablet; Z-Lig, Z-ligustilide; eNOS, endothelial NO synthase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Atherosclerosis* / drug therapy
  • Endothelial Cells / metabolism
  • Heme Oxygenase-1 / metabolism
  • Herbal Medicine
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Pharmaceutical Preparations*


  • NF-E2-Related Factor 2
  • Pharmaceutical Preparations
  • Heme Oxygenase-1