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Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells

In English

Författare

  • KY Chyu
  • PC Dimayuga
  • XN Zhao
  • Jan Nilsson
  • PK Shah
  • B Cercek

Summary, in English

We previously reported that injury-induced medial vascular smooth muscle cell (VSMC) proliferation and neointima formation in carotid arteries of inducible nitric oxide synthase knockout ( iNOS KO) mice were significantly reduced compared with wild type (WT). However, the molecular pathway underlying such differences is not known. In this in vitro study, we discovered that the AP-1/Ref-1/thioredoxin signaling pathway is altered in aortic VSMC from iNOS KO mice, which leads to reduced growth response when compared with aortic VSMC from WT mice. After equal initial seeding, the cell number after 7 days in serum medium was less in iNOS KO cells compared with WT VSMC (1.2 +/- 0.6 x 10(5) vs 3.2 +/- 1.1 x 10(5); p < 0.05). Significantly more iNOS KO cells remained in the G0/G1 phase compared with WT cells after 24-h serum treatment (82.6 +/- 13.7% vs 62.3 +/- 14.6%; p < 0.05) by cell-cycle analysis. Nuclear PCNA expression was also less in the iNOS KO cells, which was not affected by exogenous NO or superoxide. Superoxide generation after 24-h serum stimulation was less in the iNOS KO cells compared with WT cells. After 30-min serum stimulation, AP-1 DNA binding was reduced and a lack of increase in nuclear c-Jun protein was observed in iNOS KO VSMC. RT-PCR analysis confirmed a lack of inducible c-Jun mRNA after serum stimulation in the KO cells. In addition, KO cells had less nuclear reducing factor-1 (Ref-1) and serum-inducible thioredoxin protein expression. Reduced proliferative response of iNOS KO VSMC to serum treatment is associated with altered AP-1/Ref-1/thioredoxin pathway activation.

Publiceringsår

2004

Språk

Engelska

Sidor

177-183

Publikation/Tidskrift/Serie

Vascular Medicine

Volym

9

Issue

3

Dokumenttyp

Artikel i tidskrift

Förlag

SAGE Publications

Ämne

  • Cardiac and Cardiovascular Systems

Nyckelord

  • VSMC
  • Ref-1
  • proliferation
  • AP-1
  • thioredoxin
  • iNOS KO

Status

Published

Forskningsgrupp

  • Cardiovascular Research - Immunity and Atherosclerosis

ISBN/ISSN/Övrigt

  • ISSN: 1477-0377