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

Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center/David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Chyuk{at}cshs.org

Paul C Dimayuga

Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center/David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

Xiaoning Zhao

Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center/David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

Jan Nilsson

Experimental Cardiovascular Research, Department of Medicine, Lund University, University Hospital MAS, Malmö, Sweden

Prediman K Shah

Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center/David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

Bojan Cercek

Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center/David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

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 (1.2-0.6-10⁵ vs 3.2-1.1-10⁵; 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.

Key Words: AP-1 • iNOS KO • proliferation • Ref-1 • thioredoxin • VSMC

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