title: Dimethylfumarate attenuates restenosis after acute vascular injury by cell-specific and Nrf2-dependent mechanisms.
abstract: Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF-E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs. Initially, DMF increased p21 protein stability through an enhancement in Nrf2 activity without an increase in p21 mRNA. Later on, DMF stimulated p21 mRNA expression through a process dependent on p53 activity. However, heme oxygenase-1 (HO-1) or NQO1 activity, well-known target genes induced by Nrf2, were dispensable for the DMF induction of p21 protein and the effect on the VSMC proliferation. Likewise, DMF protected endothelial cells from TNF-α-induced apoptosis and the dysfunction characterized by decreased eNOS expression. With knock-down of Nrf2 or NQO1, DMF failed to prevent TNF-α-induced cell apoptosis and decreased eNOS expression. Also, CD31 expression, an endothelial specific marker, was restored in vivo by DMF. In conclusion, DMF prevented abnormal proliferation in VSMCs by G1 cell cycle arrest via p21 upregulation driven by Nrf2 and p53 activity, and had a beneficial effect on TNF-α-induced apoptosis and dysfunction in endothelial cells through Nrf2-NQO1 activity suggesting that DMF might be a therapeutic drug for patients with vascular disease.
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea.
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea ; GIST College, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea ; Research Institute of Clinical Medicine, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Faculty of Fundamental Medical Sciences, Catholic University, Daegu, Republic of Korea.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Go
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea ; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Departments of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Republic of Korea ; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005650:Fumarates; D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D000069462:Dimethyl Fumarate
keywords: Cell cycle protein; DMF, dimethylfumarate; HAECs, human aortic endothelial cells; HO-1, heme oxygenase-1; LST, late stent thrombosis; NQO1, NAD(P)H quinone oxidoreductase 1; Neointimal hyperplasia; Nrf2, nuclear-factor-E2-related factor-2; PFT-α, Pifithrin-α; PTCA, percutaneous coronary angioplasty; Reactive oxygen species; Restenosis; VSMCs, vascular smooth muscle cells; Vascular remodeling; p53 Pathway