Andrographolide inhibits NF-KB activation and attenuates neointimal hyperplasia in arterial restenosis  

作　　者：YuJiu Wang Jin Tao Wang QuanXin Fan Jian Guo Geng 

机构地区：[1]Department of Cardiac Surgery, Shandong Provincial Hospital Shandong University, Jinan 250021, China [2]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China

出　　处：《Cell Research》2007年第11期933-941,共9页细胞研究（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China （30370694, 30421005, 30623003, 30400245 and 30630036）, the Ministry of Science and Technology of China （2002CB513006, 2006CB943902 and 2006AA02Z 169）, the Chinese Acad- emy of Sciences （KSCX2-YW-R-67 and KJCX2-YW-H08） and the Shanghai Municipal Commission for Science and Technology （04JC14078, 06DZ22032, 055407035 and 058014578）.

摘　　要：The NF-kB 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-kB transcription factors, thus blocking the binding of NF-kB transcription factors to the promoters of their target genes, preventing NF-kB 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 （-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-kB 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 ofTF, E-selectin and VCAM-I was also markedly upregulated in the patient sample of thrombotic vasculitis, indicating the clinical relevance of NF-kB activation in the pathogeneses of occlusive arterial diseases. Our data thus indicate that, by the downregulation of the NF-kB 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.

关 键 词：NF-kB transcription factors ANDROGRAPHOLIDE neointimal hyperplasia arterial restenosis TF E-SELECTIN VCAM-I 

分 类 号：R543[医药卫生—心血管疾病]