title: Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia.
abstract: OBJECTIVE
  Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia.
  
  
  RESULTS
  SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-kappaB) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21(waf1/Cip1). The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ.
  
  
  CONCLUSIONS
  Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.
authors.affiliation: National Research Laboratory on Cardiovascular Stem Cell, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jung-Ju
authors.initials: JJ
authors.lastname: Sir
authors.forename: Baek-Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Soo-In
authors.initials: SI
authors.lastname: Jun
authors.forename: Kyung-Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Seok-Jae
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Yoo-Wook
authors.initials: YW
authors.lastname: Kwon
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002340:Carotid Artery Diseases / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005786:Gene Expression Regulation; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006965:Hyperplasia / Q000517:prevention & control; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D051547:Heme Oxygenase-1