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

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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
Pages (from-to)	361-371
Number of pages	11
Journal	Cell Metabolism
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2012.01.017
Publication status	Published - 1 Mar 2012

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Ashrafian_et_al_Fumarate_Is_Cardioprotective_Cell_Metabolism_2012
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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{bd5984b40cbc4395a0335b4a81edb5f5,

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",

year = "2012",

month = mar,

day = "1",

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

language = "English",

volume = "15",

pages = "361--371",

journal = "Cell Metabolism",

publisher = "Elsevier",

number = "3",

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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

PY - 2012/3/1

Y1 - 2012/3/1

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.

U2 - 10.1016/j.cmet.2012.01.017

DO - 10.1016/j.cmet.2012.01.017

M3 - Article

C2 - 22405071

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

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