The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway
Open accessAbstract
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.
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Cites
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“While Nrf2 activation is known to be cardioprotective when acutely activated (Calvert et al., 2009; Motohashi and Yamamoto, 2004; Zhang et al., 2010), there is emerging evidence that chronic Nrf2 activation results in experimental and human cardiomyopathy (Rajasekaran et al.”
BackgroundMolecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
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“Thus, although we cannot exclude other Nrf2-stabilizing influences (Rada et al., 2011), given Keap1’s sensitivity to electrophiles and its proximity to mitochondria (Lo and Hannink, 2008) (where fumarate concentrations are likely to be highest), coupled with increased succination and the findings…”
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“, 2011), support the proposal that Keap1 succination in Fh1 KO hearts is the cause of Nrf2 activation (Adam et al., 2011; Ooi et al., 2011).”
BackgroundInfluentialThe succinate receptor GPR91 in neurons has a major role in retinal angiogenesis
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Cited by
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
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Self-citationROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection
Cadenas, S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.024 · Cited by 820
A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury
Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., Krieg, T., & Murphy, M. P. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.009 · Cited by 752
Nrf2 at the heart of oxidative stress and cardiac protection
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Redox Signaling by Reactive Electrophiles and Oxidants
Parvez, S., Long, M. J. C., Poganik, J. R., & Aye, Y. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00698 · Cited by 359
Metadata
- Authors
- 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., Tennant, D. A., Land, J., Lygate, C. A., Johannsen, M., Kharbanda, R. K., Neubauer, S., Redwood, C., de Cabo, R., Ahmet, I., Talan, M., Günther, U. L., Robinson, A. J., Viant, M. R., Pollard, P. J., Tyler, D. J., & Watkins, H.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 15
- Issue
- 3
- Pages
- 361-371
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2128123270
- Cited by
- 302
- References
- 13
- FWCI
- 13.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
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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. https://doi.org/10.1016/j.cmet.2012.01.017
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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