title: Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery.
abstract: BACKGROUND
  Vascular injury activates various kinds of genes, including proto-oncogenes, growth factors, and extracellular matrix proteins. However, the significance of activation of these genes in neointimal formation is poorly understood. Angiotensin II type 1 (AT1) receptor antagonist is shown to prevent neointimal formation after vascular injury, although the mechanism is unclear. To understand the molecular mechanism of vascular thickening, we examined the effects of AT1 receptor blockade on the gene expression of proto-oncogenes, transforming growth factor-beta 1 (TGF-beta 1), and extracellular matrix proteins after vascular injury.
  
  
  RESULTS
  Endothelial denudation of the left common carotid artery in Sprague-Dawley rats was performed with a Fogarty 2F balloon catheter. TCV-116 (10 mg.kg-1.d-1), a selective nonpeptide AT1 receptor antagonist, or vehicle was administered orally to rats from 1 day before to 14 days after balloon injury. Injured left and uninjured right common carotid arteries were removed from rats at 1, 6, and 24 hours and 3, 7, and 14 days after balloon injury. Tissue mRNA levels were measured with Northern blot analysis using specific cDNA probes and corrected for 18S ribosomal RNA value. Arterial mRNAs for c-fos, c-jun, jun B, jun D, and Egr-1 increased significantly at 1 hour after balloon injury and decreased rapidly. At 6 hours, ornithine decarboxylase (ODC) mRNA expression reached the maximal levels. TGF-beta 1 and fibronectin mRNA levels started to increase at 6 hours after injury and remained enhanced until 7 days after injury. On the other hand, collagen types I, III, and IV and laminin mRNA levels were not significantly increased over 7 days. Treatment with TCV-116 significantly inhibited the induction of mRNAs for c-fos, c-jun, Egr-1, ODC, and fibronectin in injured artery, whereas the increase in TGF-beta 1 gene expression after injury was not prevented by TCV-116. Immunohistological studies indicated that TCV-116 decreased not only the intimal thickening but also the amount of these extracellular matrix proteins in the intima.
  
  
  CONCLUSIONS
  The results indicate that AT1 receptor blockade inhibits the induction of immediate-early genes, ODC, and fibronectin in rat injured artery. Thus, inhibition of intimal thickening by AT1 receptor blockade may be mediated at least in part by suppression of multiple genes related to cell growth and migration in the very early phase after vascular injury.
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: H
authors.initials: H
authors.lastname: Wanibuchi
authors.forename: K
authors.initials: K
authors.lastname: Ohta
authors.forename: A
authors.initials: A
authors.lastname: Hamaguchi
authors.forename: T
authors.initials: T
authors.lastname: Omura
authors.forename: T
authors.initials: T
authors.lastname: Yukimura
authors.forename: K
authors.initials: K
authors.lastname: Miura
authors.forename: H
authors.initials: H
authors.lastname: Iwao
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001158:Arteries / Q000378:metabolism*; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003094:Collagen / Q000032:analysis; D005353:Fibronectins / Q000032:analysis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005353:Fibronectins; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003094:Collagen; D009955:Ornithine Decarboxylase; C077793:candesartan cilexetil