Gax gene transfer inhibits vascular remodeling induced by adventitial inflammation in rabbits

Aims: Adventitial fibroblasts (AFs) and inflammation play an important role in neointimal formation and vascular remodeling. The present study was aimed to investigate the therapeutic effects and underlying mechanisms of transcriptional regulator Gax gene transfection in aortic remodeling induced by adventitial inflammation. Methods and results: Fifty rabbits fed a chow diet were randomly divided into a normal control group (n = 10) and experimental group (n = 40). All rabbits in the experimental group underwent collar placement around the abdominal aorta and intra-collar injection of lipopolysaccharide (LPS) to induce adventitial inflammation and they were further divided into model control group, saline-treated group, green fluorescence protein (Ad-GFP)-treated group and Gax gene (Ad-Gax)-treated group, respectively. Four weeks after treatment, the model control group, saline-treated group and Ad-GFP-treated group showed thickened neointima and adventitia, reduced lumen size and increased eccentricity and remodeling index of the abdominal aorta in comparison with the normal control group, whereas Ad-Gax-treated group exhibited attenuated neointimal formation and vascular remodeling (P < 0.01-0.05). The vascular expression levels of interleukin (IL)-1 beta, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, Smads, mitogen-activated protein kinases (MAPKs), integrins and nuclear factor kappa B (NF-kB) were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those in the normal control group (P < 0.01-0.05). In contrast, the local expression levels of these cytokines were substantially reduced by Ad-Gax gene transfer (P < 0.01-0.05). Similarly, the serum levels of inflammatory cytokines including C-reactive protein (CRP), transforming growth factor (TGF)-beta 1, IL-1, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, MCP-1, VCAM-1 and ICAM-1 were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those of the Ad-Gax-treated group (P < 0.01-0.05). In vitro studies showed that Gax overexpression diminished inflammatory cytokine expression in LPS-stimulated arterial fibroblasts. Conclusions: Adventitial inflammation induces vascular remodeling via the interactions of multiple inflammatory cytokines and local Gax gene transfer in vivo can significantly inhibit these interactions and thereby attenuate local inflammation and vascular remodeling. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. All rights reserved.