title: Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate.
abstract: Heme derived from hemolysis is pro-oxidative and proinflammatory and promotes vaso-occlusion in murine models of sickle cell disease (SCD), suggesting that enhanced detoxification of heme may be beneficial. Nuclear factor erythroid-2-related factor-2 (Nrf2) transcription pathway is the principal cellular defense system responding to pro-oxidative and proinflammatory stress. Dimethyl fumarate (DMF), a drug approved for treatment of multiple sclerosis, provides neuroprotection by activating Nrf2-responsive genes. We hypothesized that induction of Nrf2 with DMF would be beneficial in murine SCD models.
  
  
  
  DMF (30 mg/kg/day) or vehicle (0.08% methyl cellulose) was administered for 3-7 days to NY1DD and HbSS-Townes SCD mice. Vaso-occlusion, a hallmark of SCD, measured in sickle mice with dorsal skinfold chambers, was inhibited by DMF. The inhibitory effect of DMF was abrogated by the heme oxygenase-1 (HO-1) inhibitor tin protoporphyrin. DMF increased nuclear Nrf2 and cellular mRNA of Nrf2-responsive genes in livers and kidneys. DMF increased heme defenses, including HO-1, haptoglobin, hemopexin, and ferritin heavy chain, although plasma hemoglobin and heme levels were unchanged. DMF decreased markers of inflammation, including nuclear factor-kappa B phospho-p65, adhesion molecules, and toll-like receptor 4. DMF administered for 24 weeks to HbSS-Townes mice decreased hepatic necrosis, inflammatory cytokines, and irregularly shaped erythrocytes and increased hemoglobin F, but did not alter hematocrits, reticulocyte counts, lactate dehydrogenase, plasma heme, or spleen weights, indicating that the beneficial effects of DMF were not attributable to decreased hemolysis.
  
  
  
  These studies identify Nrf2 activation as a new therapeutic target for the treatment of SCD.
  
  
  
  DMF activates Nrf2, enhances antioxidant defenses, and inhibits inflammation and vaso-occlusion in SCD mice. Antioxid. Redox Signal. 26, 748-762.
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Fuad
authors.initials: F
authors.lastname: Abdulla
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Phong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Trevor
authors.initials: T
authors.lastname: Killeen
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Pauline
authors.initials: P
authors.lastname: Xu
authors.affiliation: 2 Veterinary Population Medicine, University of Minnesota , St. Paul, Minnesota.
authors.forename: Gerry
authors.initials: G
authors.lastname: O'Sullivan
authors.affiliation: 3 Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic/Foundation , Rochester, Minnesota.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.affiliation: 1 Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000284:Administration, Oral; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D000818:Animals; D000069462:Dimethyl Fumarate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000069462:Dimethyl Fumarate
keywords: HO-1; Nrf2; haptoglobin; hemopexin; sickle cell disease