title: Activation of Nrf2 by dimethyl fumarate improves vascular calcification.
abstract: Dimethyl fumarate (DMF) has several pharmacological benefits including immunomodulation and prevention of fibrosis, which are dependent on the NF-E2-related factor 2 (Nrf2) antioxidant pathways. Therefore, we hypothesized that DMF could attenuate vascular calcification via Nrf2 activation. Vascular calcification induced by hyperphosphataemia was significantly inhibited by DMF in vascular smooth muscle cells (VSMCs) in a dose-dependent manner. DMF-mediated Nrf2 upregulation was accompanied by the reduced expressions of genes related with osteoblast-like phenotype based on promoter activity, mRNA and protein expression, and von Kossa staining. Likewise, Nrf2 overexpression significantly decreased the formation of calcium deposit similar to the level of osteogenic staining in VSMCs, and DMF with Nrf2 knockdown failed to attenuate hyperphosphatemia induced vascular calcification. Furthermore, DMF significantly attenuated the calcification of ex vivo ring culture from both rat common carotid artery and mouse thoracic aorta as well as in vivo mouse model of Vitamin D3-induced calcification consistent with the increased Nrf2 protein levels in early stage of calcification by DMF. In conclusion, our data support that DMF stimulates Nrf2 activity to attenuate hyperphosphatamia in vitro or Vitamin D3-induced in vivo vascular calcification, which would be a beneficial effect on vascular diseases induced by oxidative stress such as vascular calcification.
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Chae-Myeong
authors.initials: CM
authors.lastname: Ha
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Kwi-Hyun
authors.initials: KH
authors.lastname: Bae
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea. Electronic address: dyjun@knu.ac.kr.
authors.forename: Do Youn
authors.initials: do Y
authors.lastname: Jun
authors.affiliation: BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Republic of Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea; Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address: leei@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D000069462:Dimethyl Fumarate; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects; D061205:Vascular Calcification / Q000188:drug therapy* / Q000473:pathology
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D000069462:Dimethyl Fumarate; D002118:Calcium
keywords: Chemical compounds; Dimethyl fumarate; Dimethyl fumarate (PubChem CID: 637568); Hyperphosphatemia; NF-E2-related factor 2; Osteoblast; Vascular calcification