title: Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation.
abstract: BACKGROUND
  Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosis-related diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury.
  
  
  RESULTS
  We found less balloon injury-induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G1 phase via inhibition of the mitogen-activated protein kinase signal transduction pathways and inhibition of phosphorylation of the retinoblastoma tumor suppressor protein.
  
  
  CONCLUSIONS
  Bilirubin and biliverdin might be potential therapeutics in vascular proliferative disorders.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. robert.oellinger@uibk.ac.at
authors.forename: Robert
authors.initials: R
authors.lastname: Ollinger
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Anna
authors.initials: A
authors.lastname: Erat
authors.forename: Alberto
authors.initials: A
authors.lastname: Froio
authors.forename: James
authors.initials: J
authors.lastname: McDaid
authors.forename: Shivraj
authors.initials: S
authors.lastname: Tyagi
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Aurelio V
authors.initials: AV
authors.lastname: Graça-Souza
authors.forename: Angela
authors.initials: A
authors.lastname: Liloia
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Bach
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D001664:Biliverdine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D011911:Rats, Gunn; D011917:Rats, Inbred Lew; D017208:Rats, Wistar
chemical_list: D001664:Biliverdine; D001663:Bilirubin