296
Views
21
CrossRef citations to date
0
Altmetric
Review

An overview of the mechanisms and novel roles of Nrf2 in cardiovascular diseases

, , , , , , , , & show all
Pages 1413-1424 | Received 16 Jan 2016, Accepted 17 Oct 2016, Published online: 31 Oct 2016

References

  • Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American heart association. Circulation. 2015;133(4):e38- e360.
  • Li B, Kim Do S, Rk Y, et al. Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells. Int J Mol Med. 2015;36(1):53–64.
  • Renaud S, De Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992;339(8808):1523–1526.
  • Moi P, Chan K, Asunis I, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91(21):9926–9930.
  • Wakabayashi N, Itoh K, Wakabayashi J, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003;35(3):238–245.
  • Chui DH, Tang W, Orkin SH. cDNA cloning of murine Nrf 2 gene, coding for a p45 NF-E2 related transcription factor. Biochem Biophys Res Commun. 1995;209(1):40–46.
  • Zhou S, Sun W, Zhang Z, et al. The role of Nrf2-mediated pathway in cardiac remodeling and heart failure. Oxid Med Cell Longev. 2014;2014:260429.
  • Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86.
  • Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.
  • Kobayashi A, Kang MI, Okawa H, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004;24(16):7130–7139.
  • Zhang DD, Lo SC, Cross JV, et al. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24(24):10941–10953.
  • Tong KI, Katoh Y, Kusunoki H, et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol. 2006;26(8):2887–2900.
  • Fukutomi T, Takagi K, Mizushima T, et al. Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol. 2014;34(5):832–846.
  • Nioi P, Nguyen T, Sherratt PJ, et al. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol. 2005;25(24):10895–10906.
  • Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009;34(4):176–188.
  • Katoh Y, Itoh K, Yoshida E, et al. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells. 2001;6(10):857–868.
  • Rada P, Rojo AI, Chowdhry S, et al. SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol. 2011;31(6):1121–1133.
  • Chowdhry S, Zhang Y, McMahon M, et al. Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene. 2013;32(32):3765–3781.
  • Cuadrado A. Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. Free Radic Biol Med. 2015;88(Pt B):147–157.
  • Rojo AI, Medina-Campos ON, Rada P, et al. Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: Role of glycogen synthase kinase-3. Free Radic Biol Med. 2012;52(2):473–487.
  • Wang H, Liu K, Geng M, et al. RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 2013;73(10):3097–3108.
  • Kansanen E, Bonacci G, Schopfer FJ, et al. Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J Biol Chem. 2011;286(16):14019–14027.
  • Ogura T, Tong KI, Mio K, et al. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci U S A. 2010;107(7):2842–2847.
  • Saito R, Suzuki T, Hiramoto K, et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol Cell Biol. 2015;36(2):271–284.
  • Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 1991;266(18):11632–11639.
  • Nguyen T, Sherratt PJ, Nioi P, et al. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem. 2005;280(37):32485–32492.
  • Narasimhan M, Patel D, Vedpathak D, et al. Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells. PLoS One. 2012;7(12):e51111.
  • Wan H, Liu Y, Li M, et al. Nrf2/Maf-binding-site-containing functional Cyp6a2 allele is associated with DDT resistance in drosophila melanogaster. Pest Manag Sci. 2014;70(7):1048–1058.
  • Li H, Yao W, Irwin MG, et al. Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1. Free Radic Biol Med. 2015;84:311–321.
  • Calvert JW, Elston M, Nicholson CK, et al. Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice. Circulation. 2010;122(1):11–19.
  • Wang H, Lai Y, Mathis BJ, et al. Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2. J Mol Cell Cardiol. 2015;84:143–153.
  • Li J, Ichikawa T, Villacorta L, et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol. 2009;29(11):1843–1850.
  • Yang L, Qu M, Wang Y, et al. Trichostatin A inhibits transforming growth factor-beta-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Mol Pharmacol. 2013;83(3):671–680.
  • Dreger H, Westphal K, Weller A, et al. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 2009;83(2):354–361.
  • Zou X, Gao J, Zheng Y, et al. Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death. Cell Death Dis. 2014;5:e1218.
  • Liu Z, Sun L, Zhu L, et al. Hydroxytyrosol protects retinal pigment epithelial cells from acrolein-induced oxidative stress and mitochondrial dysfunction. J Neurochem. 2007;103(6):2690–2700.
  • Greco T, Shafer J, Fiskum G. Sulforaphane inhibits mitochondrial permeability transition and oxidative stress. Free Radic Biol Med. 2011;51(12):2164–2171.
  • Danesi F, Philpott M, Huebner C, et al. Food-derived bioactives as potential regulators of the IL-12/IL-23 pathway implicated in inflammatory bowel diseases. Mutat Res. 2010;690(1–2):139–144.
  • Itoh K, Mochizuki M, Ishii Y, et al. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol Cell Biol. 2004;24(1):36–45.
  • Rangasamy T, Cho CY, Thimmulappa RK, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004;114(9):1248–1259.
  • Rojo AI, Innamorato NG, Martin-Moreno AM, et al. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia. 2010;58(5):588–598.
  • Qu C, Li B, Lai Y, et al. Identifying panaxynol, a natural activator of nuclear factor erythroid-2 related factor 2 (Nrf2) from American ginseng as a suppressor of inflamed macrophage-induced cardiomyocyte hypertrophy. J Ethnopharmacol. 2015;168:326–336.
  • Keleku-Lukwete N, Suzuki M, Otsuki A, et al. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc Natl Acad Sci U S A. 2015;112(39):12169–12174.
  • Zeng C, Zhong P, Zhao Y, et al. Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-kappaB both in vitro and in vivo. J Mol Cell Cardiol. 2015;79:1–12.
  • Zhang Y, Talalay P, Cho CG, et al. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A. 1992;89(6):2399–2403.
  • Wang Y, Zhang Z, Sun W, et al. Sulforaphane attenuation of type 2 diabetes-induced aortic damage was associated with the upregulation of Nrf2 expression and function. Oxid Med Cell Longev. 2014;2014:123963.
  • Zhao XD, Zhou YT, Lu XJ. Sulforaphane enhances the activity of the Nrf2-ARE pathway and attenuates inflammation in OxyHb-induced rat vascular smooth muscle cells. Inflamm Res. 2013;62(9):857–863.
  • Huang CS, Lin AH, Liu CT, et al. Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFkappaB activation. Mol Nutr Food Res. 2013;57(11):1918–1930.
  • Singh P, Sharma R, McElhanon K, et al. Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radic Biol Med. 2015;86:90–101.
  • Li Z, Galli U, Becker LE, et al. Sulforaphane protects hearts from early injury after experimental transplantation. Ann Transplant. 2013;18:558–566.
  • Bai Y, Cui W, Xin Y, et al. Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol. 2013;57:82–95.
  • Miao X, Bai Y, Sun W, et al. Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants. Nutr Metab (Lond). 2012;9(1):84.
  • Qin F, Siwik DA, Luptak I, et al. The polyphenols resveratrol and S17834 prevent the structural and functional sequelae of diet-induced metabolic heart disease in mice. Circulation. 2012;125(14):1757-1764, S1751-1756.
  • Wallerath T, Deckert G, Ternes T, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002;106(13):1652–1658.
  • Hao E, Lang F, Chen Y, et al. Resveratrol alleviates endotoxin-induced myocardial toxicity via the Nrf2 transcription factor. PLoS One. 2013;8(7):e69452.
  • Gorbunov N, Petrovski G, Gurusamy N, et al. Regeneration of infarcted myocardium with resveratrol-modified cardiac stem cells. J Cell Mol Med. 2012;16(1):174–184.
  • Cheng L, Jin Z, Zhao R, et al. Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med. 2015;8(7):10420–10428.
  • Wu ZY, Wang ZW, Hu R, et al. Role of Nrf2 signal pathway in rats with deep hypothermia ischemia/reperfusion injury undergoing remote postconditioning. Genet Mol Res. 2015;14(1):492–499.
  • Mylroie H, Dumont O, Bauer A, et al. PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovasc Res. 2015;106(3):509–519.
  • Yisireyili M, Shimizu H, Saito S, et al. Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 2013;92(24–26):1180–1185.
  • Yin X, Wang X, Fan Z, et al. Hyperbaric oxygen preconditioning attenuates myocardium ischemia-reperfusion injury through upregulation of heme oxygenase 1 expression: PI3K/Akt/Nrf2 pathway involved. J Cardiovasc Pharmacol Ther. 2015;20(4):428–438.
  • Mitra A, Ray A, Datta R, et al. Cardioprotective role of P38 MAPK during myocardial infarction via parallel activation of alpha-crystallin B and Nrf2. J Cell Physiol. 2014;229(9):1272–1282.
  • Sahu BD, Kuncha M, Rachamalla SS, et al. Lagerstroemia speciosa L attenuates apoptosis in isoproterenol-induced cardiotoxic mice by inhibiting oxidative stress: possible role of Nrf2/HO-1. Cardiovasc Toxicol. 2015;15(1):10–22.
  • Liu R, Heiss EH, Sider N, et al. Identification and characterization of [6]-shogaol from ginger as inhibitor of vascular smooth muscle cell proliferation. Mol Nutr Food Res. 2015;59(5):843–852.
  • Wang Y, Ma S, Wang Q, et al. Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci China Life Sci. 2014;57(2):201–208.
  • Yang GZ, Wang ZJ, Bai F, et al. Epigallocatechin-3-gallate protects HUVECs from PM2.5-induced oxidative stress injury by activating critical antioxidant pathways. Molecules. 2015;20(4):6626–6639.
  • Wang J, Zhang L, Zhang Y, et al. Transcriptional upregulation centra of HO-1 by EGB via the MAPKs/Nrf2 pathway in mouse C2C12 myoblasts. Toxicol In Vitro. 2015;29(2):380–388.
  • Morrissy S, Strom J, Purdom-Dickinson S, et al. NAD(P)H:quinoneoxidoreductase 1 is induced by progesterone in cardiomyocytes. Cardiovasc Toxicol. 2012;12(2):108–114.
  • Wang HJ, Lee EY, Han SJ, et al. Dual pathways of p53 mediated glucolipotoxicity-induced apoptosis of rat cardiomyoblast cell: activation of p53 proapoptosis and inhibition of Nrf2-NQO1 antiapoptosis. Metabolism. 2012;61(4):496–503.
  • Hur KY, Kim SH, Choi MA, et al. Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. Atherosclerosis. 2010;211(1):69–76.
  • Pan W, Zhang AQ, Gu W, et al. Identification of haplotype tag single nucleotide polymorphisms within the nuclear factor-kappaB family genes and their clinical relevance in patients with major trauma. Crit Care. 2015;19:95.
  • Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46(5):705–716.
  • Terra X, Palozza P, Fernandez-Larrea J, et al. Procyanidin dimer B1 and trimer C1 impair inflammatory response signalling in human monocytes. Free Radic Res. 2011;45(5):611–619.
  • Banning A, Brigelius-Flohe R. NF-kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression. Antioxid Redox Signal. 2005;7(7–8):889–899.
  • White HD, Chew DP. Acute myocardial infarction. Lancet. 2008;372(9638):570–584.
  • Li H, Xie YH, Yang Q, et al. Cardioprotective effect of paeonol and danshensu combination on isoproterenol-induced myocardial injury in rats. PLoS One. 2012;7(11):e48872.
  • Thompson RC, Allam AH, Lombardi GP, et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet. 2013;381(9873):1211–1222.
  • Chen CA, Wang TY, Varadharaj S, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature. 2010;468(7327):1115–1118.
  • Jayachandran M, Chandrasekaran B, Namasivayam N. Geraniol attenuates oxidative stress by Nrf2 activation in diet-induced experimental atherosclerosis. J Basic Clin Physiol Pharmacol. 2015;26(4):335–346.
  • Ding Y, Zhang B, Zhou K, et al. Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. Int J Cardiol. 2014;175(3):508–514.
  • Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American heart association. Circulation. 2015;131(4):e29- e322.
  • Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–1913.
  • Javkhedkar AA, Quiroz Y, Rodriguez-Iturbe B, et al. Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2015;308(10):R840- R846.
  • Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29(19):2388–2442.
  • Wang W, Li S, Wang H, et al. Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. J Mol Cell Cardiol. 2014;72:305–315.
  • GBD. 2013 mortality and causes of death collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;385(9963):117–171.
  • Wang Y, Sun W, Du B, et al. Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-kappaB. Am J Physiol Heart Circ Physiol. 2013;304(4):H567- H578.
  • Zhao YY, Wang HL, Cheng XL, et al. Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy. Sci Rep. 2015;5:12936.
  • Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol. 2010;298(3):F662- F671.
  • Pedruzzi LM, Cardozo LF, Daleprane JB, et al. Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2. J Nephrol. 2015;28(4):495–501.
  • Testa A, Leonardis D, Spoto B, et al. A polymorphism in a major antioxidant gene (Kelch-like ECH-associated protein 1) predicts incident cardiovascular events in chronic kidney disease patients: an exploratory study. J Hypertens. 2016;34(5):928–934.
  • Vaziri ND, Liu S, Farzaneh SH, et al. Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease. Free Radic Biol Med. 2015;86:374–381.
  • De Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492–2503.
  • Li P, Su L, Li X, et al. Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice. Int J Neurosci. 2015;126(6):552–559.
  • Wu KC, Liu JJ, Klaassen CD. Nrf2 activation prevents cadmium-induced acute liver injury. Toxicol Appl Pharmacol. 2012;263(1):14–20.
  • Freigang S, Ampenberger F, Spohn G, et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol. 2011;41(7):2040–2051.
  • Sawada H, Saito Y, Noguchi N. Enhanced CD36 expression changes the role of Nrf2 activation from anti-atherogenic to pro-atherogenic in apoE-deficient mice. Atherosclerosis. 2012;225(1):83–90.
  • Jiang HK, Miao Y, Wang YH, et al. Aerobic interval training protects against myocardial infarction-induced oxidative injury by enhancing antioxidase system and mitochondrial biosynthesis. Clin Exp Pharmacol Physiol. 2014;41(3):192–201.
  • Chin MP, Wrolstad D, Bakris GL, et al. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014;20(12):953–958.
  • Haghjooy Javanmard S, Ziaei A, Ziaei S, et al. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid Med Cell Longev. 2013;2013:676829.
  • Kumar H, Kim IS, More SV, et al. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep. 2014;31(1):109–139.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.