Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway

被引：238

作者：

Ashrafian, Houman ^{[1
]}

Czibik, Gabor ^{[1
]}

Bellahcene, Mohamed ^{[1
]}

Aksentijevic, Dunja ^{[1
]}

Smith, Anthony C. ^{[2
]}

Mitchell, Sarah J. ^{[3
,4
]}

Dodd, Michael S. ^{[6
]}

Kirwan, Jennifer ^{[7
]}

Byrne, Jonathan J. ^{[7
]}

Ludwig, Christian ^{[8
]}

Isackson, Henrik ^{[1
]}

Yavari, Arash ^{[1
]}

Stottrup, Nicolaj B. ^{[9
,10
]}

Contractor, Hussain ^{[1
]}

Cahill, Thomas J. ^{[1
]}

Sahgal, Natasha ^{[12
]}

Ball, Daniel R. ^{[6
]}

Birkler, Rune I. D. ^{[9
,10
]}

Hargreaves, Lain ^{[11
]}

Tennant, Daniel A. ^{[8
]}

Land, John ^{[11
]}

Lygate, Craig A. ^{[1
]}

Johannsen, Mogens ^{[9
,10
]}

Kharbanda, Rajesh K. ^{[1
]}

Neubauer, Stefan ^{[1
]}

Redwood, Charles ^{[1
]}

de Cabo, Rafael ^{[4
]}

Ahmet, Ismayil ^{[5
]}

Talan, Mark ^{[5
]}

Guenther, Ulrich L. ^{[8
]}

Robinson, Alan J. ^{[2
]}

Viant, Mark R. ^{[7
]}

Pollard, Patrick J. ^{[11
]}

Tyler, Damian J. ^{[6
]}

Watkins, Hugh ^{[1
,12
]}

机构：

[1] Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England

[2] Med Res Council Mitochondrial Biol Unit, Cambridge CB2 0XY, England

[3] Univ Sydney, Royal N Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia

[4] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA

[5] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA

[6] Univ Oxford, Dept Physiol Anat & Genet, Cardiac Metab Res Grp, Oxford OX1 3QX, England

[7] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England

[8] Univ Birmingham, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England

[9] Aarhus Univ Hosp, Skejby Hosp, Dept Cardiol, Aarhus 8200 N, Denmark

[10] Aarhus Univ Hosp, Sect Toxicol & Drug Anal, Dept Forens Med, Aarhus 8200 N, Denmark

[11] Natl Hosp Neurol, Neurometabol Unit, London WC1N 3BG, England

[12] Univ Oxford, Nuffield Dept Med, Oxford OX3 7BN, England

来源：

CELL METABOLISM | 2012年 / 15卷 / 03期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

TRICARBOXYLIC-ACID-CYCLE; C-13; MAGNETIC-RESONANCE; IN-VIVO ASSESSMENT; HEME OXYGENASE-1; RAT-HEART; KEAP1-NRF2; PATHWAY; STRESS-RESPONSE; MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY; EXPRESSION;

D O I：

10.1016/j.cmet.2012.01.017

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

引用

页码：361 / 371

页数：11

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