Abstract 119: Impact of TNF-alpha and IFN-gamma on Neointimal Formation After Vascular Injury in Mice
Background: Vascular injury initiates inflammatory responses and promotes neoinitmal formation that is a major cause of restenosis after coronary intervention. Inflammatory cytokines such as Interferon-gamma (IFN-γ) and Tumor necrosis factor-alpha (TNF-α), have been shown to be upregulated in the restenostic lesion and, therefore, might be involved in underlying mechanism of restenosis. The purpose of this study is to examine the impact of IFN-γand TNF-α on neointimal formation after vascular injury.
Methods and Results: Wire-mediated vascular injury was produced in the femoral artery of wild-type (WT) mice, IFN-γ deficient (IFN-γ−/−) mice, TNF-γ deficient (TNF-α−/−) mice, and TNF-α/IFN-γdouble-deficient (TNF-α−/−/IFN-γ−/−) mice. Histological analysis revealed that neointimal formation was drastically reduced at 28 days after the injury in TNF-α−/−/IFN-γ−/− mice compared with that in WT, IFN-γ−/−, and TNF-α−/− mice (I/M ratio, WT: 2. 3±1.47, IFN-α−/−: 2.13±0.85, TNF-α−/−: 2.19±1.19, TNF-α−/−/IFN-γ−/−: 0.85±0.42, p<0.05). No significant difference was observed in reendothelialization, determined by CD31 staining, in injured arteries among these groups. In addition, reduced expression of the proliferating cell nuclear antigen (PCNA) in neointimal lesion was detected in TNF-α−/−/IFN-γ−/− mice. In vitro experiments showed that TNF-αand IFN-γ production by lipopolysaccharide in bone marrow cells was completely inhibited in the TNF-α−/− /IFN-γ−/− mice, but there were no significant differences of MCP-1, IL-6, and IL-10 produciton between WT and TNF-α−/− /IFN-γ−/− mice.
Conclusions: These findings suggest that TNF-α and IFN-γ synergistically prevents neointimal formation after vascular injury and provide new insight into the mechanism underlying restenosis after coronary intervention.