title: Novel TNF-α receptor 1 antagonist treatment attenuates arterial inflammation and intimal hyperplasia in mice.
abstract: OBJECTIVE
  Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation.
  
  
  METHODS
  We investigated intimal hyperplasia in IL-1 receptor antagonist-deficient mice two weeks after inducing femoral artery injury in an external vascular cuff model. All mice received intraperitoneal injections of TNFR1 antagonist (PEG-R1antTNF) or normal saline twice daily for 14 days.
  
  
  RESULTS
  PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group; however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (19,671±4,274 vs. 11,440±3,292 µm(2); p=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; p=0.029), compared with saline injection. Immunostaining revealed that PEG-R1antTNF inhibits Nuclear factor-κB (NF-κB), suppressing smooth muscle cell (SMC) proliferation and decreasing chemokine and adhesion molecule expression, and thus decreasing intimal hyperplasia and inflammation.
  
  
  CONCLUSIONS
  Our data suggest that PEG-R1antTNF suppresses SMC proliferation and inflammation by inhibiting NF-κB. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.
authors.affiliation: Medical Engineering, National Defense Medical College, Saitama, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kitagaki
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kamada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Tomiharu
authors.initials: T
authors.lastname: Niida
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kujiraoka
authors.forename: Norio
authors.initials: N
authors.lastname: Ishigami
authors.forename: Miya
authors.initials: M
authors.lastname: Ishihara
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
authors.forename: Makoto
authors.initials: M
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D001167:Arteritis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000627:therapeutic use*; D019151:Peptide Library; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D010446:Peptide Fragments; D019151:Peptide Library; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha