期刊
CELL RESEARCH
卷 17, 期 11, 页码 933-941出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2007.89
关键词
NF-kappa B transcription factors; andrographolide; neointimal hyperplasia; arterial restenosis; TF; E-selectin; VCAM-1
类别
The NF-kappa B transcription factors modulate the expression of tissue factor (TF), E-selectin (CD62E) and vascular cell adhesion molecule-1 (VCAM-1), which are essential for thrombosis and inflammation. We have previously shown that andrographolide (Andro) covalently modifies the reduced cysteine 62 of p50 - a major subunit of NF-kappa B transcription factors, thus blocking the binding of NF-kappa B transcription factors to the promoters of their target genes, preventing NF-kappa B activation and inhibiting inflammation in vitro and in vivo. Here we report that Andro, but not its inactive structural analog 4H-Andro, significantly suppressed the proliferation of arterial neointima (similar to 60% reduction) in a murine model of arterial restenosis. Consistently, p50(-/-) mice manifested attenuated neointimal hyperplasia upon arterial ligation. Notably, the same dosage of Andro did not further reduce neointimal formation in p50(-/-) mice, which implicates the specificity of Andro on p50 for treating experimental arterial restenosis. The upregulation of NF-kappa B target genes, including TF, E-selectin and VCAM-1, and the increased deposition of leukocytes (mainly CD68(+) macrophages) were clearly detected within the injured arterial walls, all of which were significantly abolished by treatment with Andro or genetic deletion of p50. The expression of TF, E-selectin and VCAM-1 was also markedly upregulated in the patient sample of thrombotic vasculitis, indicating the clinical relevance of NF-kappa B activation in the pathogeneses of occlusive arterial diseases. Our data thus indicate that, by the downregulation of the NF-kappa B target genes that are critical in thrombosis and inflammation, specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and treating thrombotic arterial diseases, including neointimal hyperplasia in arterial restenosis.
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