Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.

TitleFumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.
Publication TypeJournal Article
Year of Publication2012
AuthorsAshrafian, 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
JournalCell Metab
Volume15
Issue3
Pagination361-71
Date Published2012 Mar 7
ISSN1932-7420
KeywordsAnimals, Antioxidants, Fumarate Hydratase, Fumarates, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Myocardial Infarction, NF-E2-Related Factor 2, Signal Transduction
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.

DOI10.1016/j.cmet.2012.01.017
Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2012.01.017
PubMed ID22405071
PubMed Central IDPMC3314920
Grant List075491/Z/04 / / Wellcome Trust / United Kingdom
090532 / / Wellcome Trust / United Kingdom
FS/10/002/28078 / / British Heart Foundation / United Kingdom
G0601490 / / Medical Research Council / United Kingdom
MC_U105674181 / / Medical Research Council / United Kingdom
RG/02/010 / / British Heart Foundation / United Kingdom
RG/05/005 / / British Heart Foundation / United Kingdom
RG/07/012/24110 / / British Heart Foundation / United Kingdom
RG/10/002/28187 / / British Heart Foundation / United Kingdom
/ / Medical Research Council / United Kingdom