Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

Houman Ashrafian; Gabor Czibik; Mohamed Bellahcene; Dunja Aksentijević; Anthony C. Smith; Sarah J. Mitchell; Michael S. Dodd; Jennifer Kirwan; Jonathan J. Byrne; Christian Ludwig; Henrik Isackson; Arash Yavari; Nicolaj B. Støttrup; Hussain Contractor; Thomas J. Cahill; Natasha Sahgal; Daniel R. Ball; Rune I.D. Birkler; Iain Hargreaves; Daniel A. Tennant; John Land; Craig A. Lygate; Mogens Johannsen; Rajesh K. Kharbanda; Stefan Neubauer; Charles Redwood; Rafael De Cabo; Ismayil Ahmet; Mark Talan; Ulrich L. Günther; Alan J. Robinson; Mark R. Viant; Patrick J. Pollard; Damian J. Tyler; Hugh Watkins

doi:10.1016/j.cmet.2012.01.017

Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

Houman Ashrafian^*, Gabor Czibik, Mohamed Bellahcene, Dunja Aksentijević, Anthony C. Smith, Sarah J. Mitchell, Michael S. Dodd, Jennifer Kirwan, Jonathan J. Byrne, Christian Ludwig, Henrik Isackson, Arash Yavari, Nicolaj B. Støttrup, Hussain Contractor, Thomas J. Cahill, Natasha Sahgal, Daniel R. Ball, Rune I.D. Birkler, Iain Hargreaves, Daniel A. TennantJohn Land, Craig A. Lygate, Mogens Johannsen, Rajesh K. Kharbanda, Stefan Neubauer, Charles Redwood, Rafael De Cabo, Ismayil Ahmet, Mark Talan, Ulrich L. Günther, Alan J. Robinson, Mark R. Viant, Patrick J. Pollard, Damian J. Tyler, Hugh Watkins

^*Corresponding author for this work

Institute of Chemistry and Metabolomics

154 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cell Metabolism
Volume	15
Issue number	3
Pages (from-to)	361-371
Number of pages	11
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2012.01.017
Publication status	Published - 07.03.2012

Funding

H.A. and H.W. are supported by the Oxford British Heart Foundation Centre of Research Excellence Award, and the the British Heart Foundation (BHF Grant RG/02/010). A.J.R. and A.C.S. are supported by the Medical Research Council, UK. D.A. and S.N. are supported by the British Heart Foundation Programme Grant RG/05/005. M.S.D., D.R.B., and D.J.T. are supported by research grants from the British Heart Foundation, the Medical Research Council, Oxford Instruments Molecular Biotools, and GE Healthcare. N.S.'s work is supported by the Core Award Grant 075491/Z/04 from the Wellcome Trust. N.B.S. is supported by the Fondation Leducq (06CVD) and the Lundbeck Foundation. P.J.P. is in receipt of a Beit Memorial Fellowship. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (1016439). The Thermo Scientific LTQ FT Ultra and Bruker NMR spectrometers used here were obtained through the Birmingham Science City Translational Medicine project, with support from Advantage West Midlands; the NMR spectrometer was further supported by the Wolfson Foundation. This study was also funded in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. We gratefully acknowledge and thank Dr. Reza Morovat, consultant clinical biochemist at the Oxford Radcliffe NHS Trust, Oxford; and Dawn Phillips-Boyer and Dawn Nines for their excellent animal care and assistance.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2012.01.017

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Ashrafian, H., Czibik, G., Bellahcene, M., Aksentijević, D., Smith, A. C., Mitchell, S. J., Dodd, M. S., Kirwan, J., Byrne, J. J., Ludwig, C., Isackson, H., Yavari, A., Støttrup, N. B., Contractor, H., Cahill, T. J., Sahgal, N., Ball, D. R., Birkler, R. I. D., Hargreaves, I., ... Watkins, H. (2012). Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metabolism, 15(3), 361-371. https://doi.org/10.1016/j.cmet.2012.01.017

@article{829b6e31a00648baa90860a8b861a61b,

title = "Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway",

abstract = "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.",

author = "Houman Ashrafian and Gabor Czibik and Mohamed Bellahcene and Dunja Aksentijevi{\'c} and Smith, \{Anthony C.\} and Mitchell, \{Sarah J.\} and Dodd, \{Michael S.\} and Jennifer Kirwan and Byrne, \{Jonathan J.\} and Christian Ludwig and Henrik Isackson and Arash Yavari and St{\o}ttrup, \{Nicolaj B.\} and Hussain Contractor and Cahill, \{Thomas J.\} and Natasha Sahgal and Ball, \{Daniel R.\} and Birkler, \{Rune I.D.\} and Iain Hargreaves and Tennant, \{Daniel A.\} and John Land and Lygate, \{Craig A.\} and Mogens Johannsen and Kharbanda, \{Rajesh K.\} and Stefan Neubauer and Charles Redwood and \{De Cabo\}, Rafael and Ismayil Ahmet and Mark Talan and G{\"u}nther, \{Ulrich L.\} and Robinson, \{Alan J.\} and Viant, \{Mark R.\} and Pollard, \{Patrick J.\} and Tyler, \{Damian J.\} and Hugh Watkins",

note = "Funding Information: H.A. and H.W. are supported by the Oxford British Heart Foundation Centre of Research Excellence Award, and the the British Heart Foundation (BHF Grant RG/02/010). A.J.R. and A.C.S. are supported by the Medical Research Council, UK. D.A. and S.N. are supported by the British Heart Foundation Programme Grant RG/05/005. M.S.D., D.R.B., and D.J.T. are supported by research grants from the British Heart Foundation, the Medical Research Council, Oxford Instruments Molecular Biotools, and GE Healthcare. N.S.'s work is supported by the Core Award Grant 075491/Z/04 from the Wellcome Trust. N.B.S. is supported by the Fondation Leducq (06CVD) and the Lundbeck Foundation. P.J.P. is in receipt of a Beit Memorial Fellowship. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (1016439). The Thermo Scientific LTQ FT Ultra and Bruker NMR spectrometers used here were obtained through the Birmingham Science City Translational Medicine project, with support from Advantage West Midlands; the NMR spectrometer was further supported by the Wolfson Foundation. This study was also funded in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. We gratefully acknowledge and thank Dr. Reza Morovat, consultant clinical biochemist at the Oxford Radcliffe NHS Trust, Oxford; and Dawn Phillips-Boyer and Dawn Nines for their excellent animal care and assistance. Copyright: Copyright 2012 Elsevier B.V., All rights reserved.",

year = "2012",

month = mar,

day = "7",

doi = "10.1016/j.cmet.2012.01.017",

language = "English",

volume = "15",

pages = "361--371",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "3",

}

Ashrafian, H, Czibik, G, Bellahcene, M, Aksentijević, D, Smith, AC, Mitchell, SJ, Dodd, MS, Kirwan, J, Byrne, JJ, Ludwig, C, Isackson, H, Yavari, A, Støttrup, NB, Contractor, H, Cahill, TJ, Sahgal, N, Ball, DR, Birkler, RID, Hargreaves, I, Tennant, DA, Land, J, Lygate, CA, Johannsen, M, Kharbanda, RK, Neubauer, S, Redwood, C, De Cabo, R, Ahmet, I, Talan, M, Günther, UL, Robinson, AJ, Viant, MR, Pollard, PJ, Tyler, DJ & Watkins, H 2012, 'Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway', Cell Metabolism, vol. 15, no. 3, pp. 361-371. https://doi.org/10.1016/j.cmet.2012.01.017

TY - JOUR

T1 - Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

AU - Ashrafian, Houman

AU - Czibik, Gabor

AU - Bellahcene, Mohamed

AU - Aksentijević, Dunja

AU - Smith, Anthony C.

AU - Mitchell, Sarah J.

AU - Dodd, Michael S.

AU - Kirwan, Jennifer

AU - Byrne, Jonathan J.

AU - Ludwig, Christian

AU - Isackson, Henrik

AU - Yavari, Arash

AU - Støttrup, Nicolaj B.

AU - Contractor, Hussain

AU - Cahill, Thomas J.

AU - Sahgal, Natasha

AU - Ball, Daniel R.

AU - Birkler, Rune I.D.

AU - Hargreaves, Iain

AU - Tennant, Daniel A.

AU - Land, John

AU - Lygate, Craig A.

AU - Johannsen, Mogens

AU - Kharbanda, Rajesh K.

AU - Neubauer, Stefan

AU - Redwood, Charles

AU - De Cabo, Rafael

AU - Ahmet, Ismayil

AU - Talan, Mark

AU - Günther, Ulrich L.

AU - Robinson, Alan J.

AU - Viant, Mark R.

AU - Pollard, Patrick J.

AU - Tyler, Damian J.

AU - Watkins, Hugh

N1 - Funding Information: H.A. and H.W. are supported by the Oxford British Heart Foundation Centre of Research Excellence Award, and the the British Heart Foundation (BHF Grant RG/02/010). A.J.R. and A.C.S. are supported by the Medical Research Council, UK. D.A. and S.N. are supported by the British Heart Foundation Programme Grant RG/05/005. M.S.D., D.R.B., and D.J.T. are supported by research grants from the British Heart Foundation, the Medical Research Council, Oxford Instruments Molecular Biotools, and GE Healthcare. N.S.'s work is supported by the Core Award Grant 075491/Z/04 from the Wellcome Trust. N.B.S. is supported by the Fondation Leducq (06CVD) and the Lundbeck Foundation. P.J.P. is in receipt of a Beit Memorial Fellowship. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (1016439). The Thermo Scientific LTQ FT Ultra and Bruker NMR spectrometers used here were obtained through the Birmingham Science City Translational Medicine project, with support from Advantage West Midlands; the NMR spectrometer was further supported by the Wolfson Foundation. This study was also funded in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. We gratefully acknowledge and thank Dr. Reza Morovat, consultant clinical biochemist at the Oxford Radcliffe NHS Trust, Oxford; and Dawn Phillips-Boyer and Dawn Nines for their excellent animal care and assistance. Copyright: Copyright 2012 Elsevier B.V., All rights reserved.

PY - 2012/3/7

Y1 - 2012/3/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84863244462

U2 - 10.1016/j.cmet.2012.01.017

DO - 10.1016/j.cmet.2012.01.017

M3 - Journal articles

C2 - 22405071

AN - SCOPUS:84863244462

SN - 1550-4131

VL - 15

SP - 361

EP - 371

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

Abstract

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