Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.
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 (K...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2012
|
| _version_ | 1797103135043354624 |
|---|---|
| author | Ashrafian, H Czibik, G Bellahcene, M Aksentijević, D Smith, A Mitchell, S Dodd, M Kirwan, J Byrne, J Ludwig, C Isackson, H Yavari, A Støttrup, N Contractor, H Cahill, T Sahgal, N Ball, DR Birkler, R Hargreaves, I Tennant, D Land, J Lygate, C Johannsen, M Kharbanda, R Neubauer, S |
| author_facet | Ashrafian, H Czibik, G Bellahcene, M Aksentijević, D Smith, A Mitchell, S Dodd, M Kirwan, J Byrne, J Ludwig, C Isackson, H Yavari, A Støttrup, N Contractor, H Cahill, T Sahgal, N Ball, DR Birkler, R Hargreaves, I Tennant, D Land, J Lygate, C Johannsen, M Kharbanda, R Neubauer, S |
| author_sort | Ashrafian, H |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:15:48Z |
| format | Journal article |
| id | oxford-uuid:f10aaa2a-c2fe-4bb7-9a09-98e5842ecde2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:15:48Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:f10aaa2a-c2fe-4bb7-9a09-98e5842ecde22022-03-27T11:52:54ZFumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f10aaa2a-c2fe-4bb7-9a09-98e5842ecde2EnglishSymplectic Elements at Oxford2012Ashrafian, HCzibik, GBellahcene, MAksentijević, DSmith, AMitchell, SDodd, MKirwan, JByrne, JLudwig, CIsackson, HYavari, AStøttrup, NContractor, HCahill, TSahgal, NBall, DRBirkler, RHargreaves, ITennant, DLand, JLygate, CJohannsen, MKharbanda, RNeubauer, SThe 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. |
| spellingShingle | Ashrafian, H Czibik, G Bellahcene, M Aksentijević, D Smith, A Mitchell, S Dodd, M Kirwan, J Byrne, J Ludwig, C Isackson, H Yavari, A Støttrup, N Contractor, H Cahill, T Sahgal, N Ball, DR Birkler, R Hargreaves, I Tennant, D Land, J Lygate, C Johannsen, M Kharbanda, R Neubauer, S Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title | Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title_full | Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title_fullStr | Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title_full_unstemmed | Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title_short | Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. |
| title_sort | fumarate is cardioprotective via activation of the nrf2 antioxidant pathway |
| work_keys_str_mv | AT ashrafianh fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT czibikg fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT bellahcenem fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT aksentijevicd fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT smitha fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT mitchells fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT doddm fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT kirwanj fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT byrnej fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT ludwigc fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT isacksonh fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT yavaria fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT støttrupn fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT contractorh fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT cahillt fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT sahgaln fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT balldr fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT birklerr fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT hargreavesi fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT tennantd fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT landj fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT lygatec fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT johannsenm fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT kharbandar fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway AT neubauers fumarateiscardioprotectiveviaactivationofthenrf2antioxidantpathway |