title: Butylated hydroxyanisole stimulates heme oxygenase-1 gene expression and inhibits neointima formation in rat arteries.
abstract: OBJECTIVE
  Butylated hydroxyanisole (BHA) is a synthetic phenolic compound that is a potent inducer of phase II genes. Since heme oxygenase-1 (HO-1) is a vasoprotective protein that is upregulated by phase II inducers, the present study examined the effects of BHA on HO-1 gene expression and vascular smooth muscle cell proliferation.
  
  
  METHODS
  The regulation of HO-1 gene expression and vascular cell growth by BHA was studied in cultured rat aortic smooth muscle cells and in balloon injured rat carotid arteries.
  
  
  RESULTS
  Treatment of cultured smooth muscle cells with BHA stimulated the expression of HO-1 protein, mRNA and promoter activity in a time- and concentration-dependent manner. BHA-mediated HO-1 expression was dependent on the activation of NF-E2-related factor-2 by p38 mitogen-activated protein kinase. BHA also inhibited cell cycle progression and DNA synthesis in an HO-1-dependent manner. In addition, the local perivascular delivery of BHA immediately after arterial injury of rat carotid arteries induced HO-1 protein expression and markedly attenuated neointima formation.
  
  
  CONCLUSIONS
  These studies demonstrate that BHA stimulates HO-1 gene expression in vascular smooth muscle cells, and that the induction of HO-1 contributes to the antiproliferative actions of this phenolic antioxidant. BHA represents a potentially novel therapeutic agent in treating or preventing vasculoproliferative disease.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Liu
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Azam
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: Diana
authors.initials: D
authors.lastname: Ensenat
authors.forename: Amit N
authors.initials: AN
authors.lastname: Keswani
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Durante
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001158:Arteries; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; D002083:Butylated Hydroxyanisole; D051547:Heme Oxygenase-1