Abstract 12797: Deficiency of IκBNS Enhances Nuclear Factor-κB Activity and Promotes Neointimal Formation in Mice After Injury
Background: Nuclear factor-κB (NF-κB) plays a central role in mediating cytokines, cell adhesion molecules, and other proteins of immunity in cell types resident to the plaque microenvironment, ie, endothelial cells, smooth muscle cells and macrophages. Previous report demonstrated that IκBNS has an inhibitory effect on NF-κB activity in murine macrophages, and might also regulate NF-κB activity in those cells under inflammatory conditions. However, the role of IκBNS in arterial inflammation and intimal hyperplasia is poorly understood.
Methods and Results: We investigated neointimal formation in IκBNS-deficient (IκBNS−/−; C57BL/6 background) and wild-type (IκBNS+/+) mice two weeks after inducing femoral artery injury with an external vascular cuff model. The area of intima and media were measured, and intima/media ratio was calculated. Furthermore, phosphorylation of NF-κB(activated NF-κB), proliferating cell nuclear antigen(PCNA), and cytokine production were investigated by immunohistochemistry. The mean intimal area and the intima/media ratio of IκBNS−/− mice increased 89% (8,066 ± 1,141 [n=10] vs 4,267 ± 1,095 μm2[n=10]; p=0.027) and 100% (0.72 ± 0.13 vs 0.36 ± 0.09; p=0.032) compared with IκBNS+/+ mice. No significant differences were observed in the medial area between the two groups. Immunohistochemistory revealed that the NF-κB index (percentage of positive nuclei per total nuclei) in the intima of IκBNS−/− mice was 5.1-fold higher(7.1 ± 1.1 vs 1.4 ± 0.8% p=0.008) than that of IκBNS+/+ mice at 7 days and the PCNA index in the intima of IκBNS−/− mice was also 5.4-fold higher(17.3 ± 4.7 vs 3.2 ± 1.9% p=0.024) compared with IκBNS+/+ mice at 14 days after injury. Moreover, TNF-α and IL-6 were more strongly expressed in the arteries of IκBNS−/− mice than those of IκBNS+/+ mice at 7 and 14 days after injury. These data suggest that deficiency of IκBNS promotes neointimal formation by enhancing NF-κB activity and subsequent pro-inflammatory cytokine production after injury.
Conclusions: IκBNS might serve as a negative regulator of NF-κB in injured artery, and may suppress intimal hyperplasia in the arterial occlusive diseases, such as atherosclerosis, and restenosis after angioplasty.
- © 2010 by American Heart Association, Inc.