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Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway

2012; Cell Press; Volume: 15; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2012.01.017

1932-7420

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

Vitamin C and Antioxidants Research

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.