title: The role of Nrf2-mediated pathway in cardiac remodeling and heart failure.
abstract: Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.
authors.affiliation: The Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
authors.forename: Shanshan
authors.identifier: 0000-0003-1689-0266
authors.initials: S
authors.lastname: Zhou
authors.affiliation: The Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Sun
authors.affiliation: The Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D048909:Diabetes Complications; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006973:Hypertension / Q000150:complications; D007511:Ischemia / Q000150:complications; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species
references.citation: J Card Fail. 2009 Sep;15(7):616-28
references.pmid: 19700139
references.citation: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2237-45
references.pmid: 16844917
references.citation: J Mol Cell Cardiol. 2009 Jan;46(1):47-58
references.pmid: 19007787
references.citation: Circ Res. 2009 Jul 2;105(1):70-9
references.pmid: 19478205
references.citation: J Cardiovasc Electrophysiol. 1999 Nov;10(11):1553-6
references.pmid: 10571375
references.citation: J Cell Physiol. 2006 Oct;209(1):1-7
references.pmid: 16826603
references.citation: Vasc Health Risk Manag. 2007;3(5):629-37
references.pmid: 18078014
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:89-116
references.pmid: 16968214
references.citation: Hypertension. 2014 Jan;63(1):80-7
references.pmid: 24101662
references.citation: Proc Biol Sci. 2009 May 22;276(1663):1737-45
references.pmid: 19324792
references.citation: Diabetes. 2005 Mar;54(3):778-84
references.pmid: 15734856
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H48-59
references.pmid: 17322421
references.citation: Circulation. 2010 May 4;121(17):1912-25
references.pmid: 20404253
references.citation: Hypertension. 2007 Feb;49(2):241-8
references.pmid: 17190878
references.citation: Ann Intern Med. 1986 Jul;105(1):67-81
references.pmid: 3521429
references.citation: Cardiovasc Res. 2011 Jul 15;91(2):320-9
references.pmid: 21406596
references.citation: Am J Physiol Heart Circ Physiol. 2013 Dec 1;305(11):H1658-67
references.pmid: 24043257
references.citation: Cardiovasc Res. 2005 Jul 1;67(1):21-9
references.pmid: 15896727
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:243-62
references.pmid: 17002598
references.citation: Mol Cell Biol. 2004 Aug;24(16):7130-9
references.pmid: 15282312
references.citation: J Mol Cell Cardiol. 2010 Oct;49(4):576-86
references.pmid: 20685357
references.citation: Nature. 2000 Apr 13;404(6779):787-90
references.pmid: 10783895
references.citation: J Mol Cell Cardiol. 2013 Apr;57:82-95
references.pmid: 23353773
references.citation: Arch Toxicol. 2011 Dec;85(12):1509-16
references.pmid: 21465251
references.citation: Exp Diabetes Res. 2012;2012:216512
references.pmid: 22645602
references.citation: J Mol Cell Cardiol. 2006 Nov;41(5):876-84
references.pmid: 16973174
references.citation: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H688-94
references.pmid: 12124217
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1029-37
references.pmid: 11076792
references.citation: Cell Physiol Biochem. 2011;28(1):25-32
references.pmid: 21865845
references.citation: Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
references.pmid: 9240432
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15565-70
references.pmid: 20713697
references.citation: Am J Hypertens. 2008 Oct;21(10):1129-36
references.pmid: 18756259
references.citation: Pathophysiology. 2000 Sep;7(3):153-163
references.pmid: 10996508
references.citation: J Biol Chem. 1997 Jun 27;272(26):16490-7
references.pmid: 9195958
references.citation: Antioxid Redox Signal. 2003 Dec;5(6):731-40
references.pmid: 14588146
references.citation: Hypertension. 2008 Jan;51(1):19-25
references.pmid: 17998475
references.citation: Biochem J. 2003 May 1;371(Pt 3):887-95
references.pmid: 12570874
references.citation: Diabetes. 2000 Nov;49(11):1939-45
references.pmid: 11078463
references.citation: Nucleic Acids Res. 1998 Jan 15;26(2):512-20
references.pmid: 9421508
references.citation: J Biol Chem. 2012 Sep 28;287(40):33720-32
references.pmid: 22879597
references.citation: J Mol Cell Cardiol. 1999 Aug;31(8):1581-9
references.pmid: 10423355
references.citation: Oxid Med Cell Longev. 2013;2013:919313
references.pmid: 23533698
references.citation: Cell Metab. 2012 Mar 7;15(3):361-71
references.pmid: 22405071
references.citation: Cardiovasc Toxicol. 2008 Summer;8(2):71-85
references.pmid: 18463988
references.citation: Thromb Res. 2008;122(6):820-5
references.pmid: 18377959
references.citation: Toxicol Mech Methods. 2012 Jun;22(5):359-66
references.pmid: 22394344
references.citation: Int J Mol Sci. 2013 Jan 28;14(2):2684-706
references.pmid: 23358254
references.citation: Cardiovasc Res. 2009 Jul 15;83(2):269-76
references.pmid: 19176600
references.citation: Pharmacol Res. 2010 Apr;61(4):342-8
references.pmid: 19948220
references.citation: Cardiovasc Res. 2009 Jul 15;83(2):354-61
references.pmid: 19351736
references.citation: PLoS One. 2013 Sep 24;8(9):e75927
references.pmid: 24086665
references.citation: Mol Cell Biol. 2008 Apr;28(8):2758-70
references.pmid: 18268004
references.citation: Mol Cell Biochem. 2008 Oct;317(1-2):43-50
references.pmid: 18581202
references.citation: Free Radic Biol Med. 2013 Dec;65:897-907
references.pmid: 23994772
references.citation: Croat Med J. 2013 Apr;54(2):171-9
references.pmid: 23630144
references.citation: Circ Res. 2009 Aug 14;105(4):365-74
references.pmid: 19608979
references.citation: Free Radic Biol Med. 2011 Apr 1;50(7):777-93
references.pmid: 21236334
references.citation: Free Radic Biol Med. 2008 Jul 1;45(1):18-31
references.pmid: 18439435
references.citation: J Appl Physiol (1985). 2011 Nov;111(5):1431-40
references.pmid: 21836049
references.citation: Free Radic Biol Med. 2008 Sep 15;45(6):855-65
references.pmid: 18638546
references.citation: Basic Res Cardiol. 2013 Jul;108(4):359
references.pmid: 23740217
references.citation: Antioxid Redox Signal. 2007 Jun;9(6):623-52
references.pmid: 17511580
references.citation: Biochem Pharmacol. 2013 Jan 15;85(2):223-33
references.pmid: 23142711
references.citation: Curr Pharm Biotechnol. 2012 Jan;13(1):97-114
references.pmid: 21470157
references.citation: J Cell Mol Med. 2012 Jan;16(1):174-84
references.pmid: 21352470
references.citation: Circ Res. 2000 Dec 8;87(12):1172-9
references.pmid: 11110775
references.citation: Br J Pharmacol. 1998 Jun;124(3):425-7
references.pmid: 9647462
references.citation: Free Radic Biol Med. 2005 Jul 1;39(1):1-25
references.pmid: 15925276
references.citation: J Cardiovasc Pharmacol. 1991 Apr;17(4):678-83
references.pmid: 1711638
references.citation: Biochem Biophys Res Commun. 1998 Sep 29;250(3):653-6
references.pmid: 9784401
references.citation: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1843-50
references.pmid: 19592468
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):414-26
references.pmid: 14962473
references.citation: J Biol Chem. 1999 Mar 5;274(10):6443-52
references.pmid: 10037736
references.citation: Diabetes. 2006 Mar;55(3):798-805
references.pmid: 16505246
references.citation: Cardiovasc Res. 1992 Apr;26(4):347-50
references.pmid: 1638565
references.citation: J Tissue Eng Regen Med. 2013 Apr;7(4):302-11
references.pmid: 22213742
references.citation: Pharmacol Ther. 2014 Jun;142(3):375-415
references.pmid: 24462787
references.citation: J Mol Cell Cardiol. 1996 Aug;28(8):1759-67
references.pmid: 8877785
references.citation: J Am Coll Cardiol. 2006 Aug 15;48(4):824-32
references.pmid: 16904556
references.citation: PLoS One. 2013;8(3):e58371
references.pmid: 23505496
references.citation: Cardiovasc Toxicol. 2001;1(3):181-93
references.pmid: 12213971
references.citation: Circ Res. 2001 May 25;88(10):1088-94
references.pmid: 11375280
references.citation: Cell Biol Int. 2008 Oct;32(10):1256-64
references.pmid: 18692581
references.citation: J Pharmacol Exp Ther. 2012 Nov;343(2):468-78
references.pmid: 22915767
references.citation: Hum Genet. 2002 Jul;111(1):1-8
references.pmid: 12136229
references.citation: J Card Fail. 2012 Mar;18(3):253-61
references.pmid: 22385947
references.citation: Int J Mol Med. 2013 Nov;32(5):1011-20
references.pmid: 23982489
references.citation: J Cell Mol Med. 2010 Sep;14(9):2235-9
references.pmid: 20716127
references.citation: Cardiovasc Drugs Ther. 2012 Dec;26(6):457-65
references.pmid: 22990325
references.citation: Cardiovasc Res. 2006 Jul 15;71(2):208-15
references.pmid: 16631149
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):978-92
references.pmid: 21627987
references.citation: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):88-98
references.pmid: 16487041
references.citation: Cardiovasc Res. 2013 Dec 1;100(3):511-9
references.pmid: 24189624
references.citation: Diabetes. 2002 Jun;51(6):1938-48
references.pmid: 12031984
references.citation: Free Radic Biol Med. 2008 Apr 1;44(7):1305-13
references.pmid: 18206658
references.citation: Oxid Med Cell Longev. 2013;2013:306073
references.pmid: 23533688
references.citation: Mol Pharmacol. 2014 May;85(5):682-91
references.pmid: 24550138
references.citation: Hypertension. 2008 Jun;51(6):1570-7
references.pmid: 18426999
references.citation: Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H412-9
references.pmid: 10666070
references.citation: Curr Med Chem. 2007;14(20):2193-203
references.pmid: 17691957
references.citation: FASEB J. 2006 Apr;20(6):661-9
references.pmid: 16581974
references.citation: J Mol Cell Cardiol. 1991 Aug;23(8):899-918
references.pmid: 1942091
references.citation: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):99-106
references.pmid: 16487042
references.citation: Circulation. 2001 Mar 27;103(12):1695-701
references.pmid: 11273999
references.citation: Am J Physiol Heart Circ Physiol. 2013 May;304(9):H1215-24
references.pmid: 23479260
references.citation: Am J Physiol Heart Circ Physiol. 2013 Feb 15;304(4):H567-78
references.pmid: 23220333
references.citation: Free Radic Biol Med. 2007 Aug 1;43(3):397-407
references.pmid: 17602955
references.citation: J Biomed Sci. 2010 Oct 07;17:80
references.pmid: 20925964
references.citation: PLoS One. 2012;7(9):e44899
references.pmid: 23028668
references.citation: Genes Dev. 1999 Jan 1;13(1):76-86
references.pmid: 9887101
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):29-38
references.pmid: 15539615
references.citation: Circ Res. 2006 Oct 27;99(9):924-32
references.pmid: 17068300
references.citation: Circ Res. 1993 Jun;72(6):1293-9
references.pmid: 8495557
references.citation: Blood Press. 2008;17(2):70-7
references.pmid: 18568695
references.citation: Circ Cardiovasc Imaging. 2013 May 1;6(3):478-86
references.pmid: 23536266
references.citation: Toxicol Appl Pharmacol. 2014 Jan 1;274(1):107-16
references.pmid: 24211725
references.citation: Cardiovasc Res. 2005 Oct 1;68(1):26-36
references.pmid: 16009356
references.citation: Oxid Med Cell Longev. 2011;2011:293769
references.pmid: 21912722
references.citation: Circulation. 2003 Feb 25;107(7):926-8
references.pmid: 12600900
references.citation: Tissue Cell. 2010 Aug;42(4):217-22
references.pmid: 20684837
references.citation: Mol Aspects Med. 2009 Feb-Apr;30(1-2):1-12
references.pmid: 18796312
references.citation: Biol Pharm Bull. 2006 May;29(5):1042-5
references.pmid: 16651743
references.citation: Eur J Pharmacol. 2006 Aug 21;544(1-3):118-25
references.pmid: 16859669
references.citation: J Biochem Mol Toxicol. 2012 Jul;26(7):264-9
references.pmid: 22730333
references.citation: Oxid Med Cell Longev. 2013;2013:104308
references.pmid: 23691261
references.citation: Adv Enzyme Regul. 2006;46:113-40
references.pmid: 16887173
references.citation: Trends Biochem Sci. 2011 Jan;36(1):30-8
references.pmid: 20728362
references.citation: Drug Metabol Drug Interact. 2000;17(1-4):3-22
references.pmid: 11201301
references.citation: Diabetes. 2005 Mar;54(3):803-10
references.pmid: 15734859
references.citation: Biochem Biophys Res Commun. 2007 Jul 20;359(1):27-33
references.pmid: 17531194
references.citation: Arch Toxicol. 2011 May;85(5):525-35
references.pmid: 21046361
references.citation: Expert Rev Mol Med. 2011 Mar 30;13:e11
references.pmid: 21450123
references.citation: J Nutr Biochem. 2013 Sep;24(9):1580-6
references.pmid: 23528973
references.citation: J Pathol. 2002 Jun;197(2):230-7
references.pmid: 12015748
references.citation: Circulation. 2004 Feb 3;109(4):544-9
references.pmid: 14744974
references.citation: Free Radic Biol Med. 2011 Jul 1;51(1):205-15
references.pmid: 21554947
references.citation: Circulation. 2002 Feb 5;105(5):602-7
references.pmid: 11827926
references.citation: Lab Invest. 2009 Jul;89(7):782-90
references.pmid: 19398959
references.citation: J Am Coll Cardiol. 2005 Oct 4;46(7):1339-50
references.pmid: 16198853
references.citation: Circ Res. 2001 Jul 20;89(2):168-73
references.pmid: 11463724
references.citation: FEBS Lett. 2005 Jun 6;579(14):3029-36
references.pmid: 15896789
references.citation: Mol Cell Biochem. 2013 Jan;372(1-2):169-79
references.pmid: 23010891
references.citation: Cardiovasc Res. 2009 Feb 15;81(3):482-90
references.pmid: 19050008
references.citation: Acta Biochim Biophys Sin (Shanghai). 2010 Apr;42(4):253-8
references.pmid: 20383463
references.citation: Dis Model Mech. 2013 Jul;6(4):1012-20
references.pmid: 23592614
references.citation: Drug Discov Today. 2006 Jun;11(11-12):524-33
references.pmid: 16713904
references.citation: Free Radic Biol Med. 1992 Sep;13(3):221-30
references.pmid: 1505779
references.citation: Free Radic Biol Med. 1992;13(2):137-42
references.pmid: 1516840
references.citation: Semin Oncol. 2013 Apr;40(2):186-98
references.pmid: 23540744
references.citation: Circulation. 2002 Mar 12;105(10):1195-201
references.pmid: 11889013
references.citation: Curr Med Chem. 2013;20(37):4680-93
references.pmid: 23834171
references.citation: Diabetes. 2011 Feb;60(2):625-33
references.pmid: 21270272
references.citation: FASEB J. 2006 Jul;20(9):1546-8
references.pmid: 16720735
references.citation: Circulation. 1987 Aug;76(2):458-68
references.pmid: 3111744
references.citation: Free Radic Biol Med. 2010 Mar 15;48(6):749-62
references.pmid: 20045723
references.citation: Circulation. 2004 Jul 20;110(3):309-16
references.pmid: 15226216
references.citation: Circulation. 1997 Nov 4;96(9 Suppl):II-216-20
references.pmid: 9386101
references.citation: Mol Aspects Med. 2011 Aug;32(4-6):234-46
references.pmid: 22020111