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.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, UK. houman.ashrafian@cardiov.ox.ac.uk
authors.forename: Houman
authors.initials: H
authors.lastname: Ashrafian
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bellahcene
authors.forename: Dunja
authors.initials: D
authors.lastname: Aksentijević
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Smith
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dodd
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirwan
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Byrne
authors.forename: Christian
authors.initials: C
authors.lastname: Ludwig
authors.forename: Henrik
authors.initials: H
authors.lastname: Isackson
authors.forename: Arash
authors.initials: A
authors.lastname: Yavari
authors.forename: Nicolaj B
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Hussain
authors.initials: H
authors.lastname: Contractor
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cahill
authors.forename: Natasha
authors.initials: N
authors.lastname: Sahgal
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Ball
authors.forename: Rune I D
authors.initials: RI
authors.lastname: Birkler
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Tennant
authors.forename: John
authors.initials: J
authors.lastname: Land
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.forename: Mogens
authors.initials: M
authors.lastname: Johannsen
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kharbanda
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Charles
authors.initials: C
authors.lastname: Redwood
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Ismayil
authors.initials: I
authors.lastname: Ahmet
authors.forename: Mark
authors.initials: M
authors.lastname: Talan
authors.forename: Ulrich L
authors.initials: UL
authors.lastname: Günther
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robinson
authors.forename: Mark R
authors.initials: MR
authors.lastname: Viant
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D000069462:Dimethyl Fumarate; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics; D005650:Fumarates / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009203:Myocardial Infarction / Q000235:genetics / Q000517:prevention & control; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D000975:Antioxidants; D005650:Fumarates; D051267:NF-E2-Related Factor 2; D005649:Fumarate Hydratase; D000069462:Dimethyl Fumarate