title: Andrographolide inhibits NF-kappaBeta activation and attenuates neointimal hyperplasia in arterial restenosis.
abstract: The NF-kappaBeta 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-kappaBeta transcription factors, thus blocking the binding of NF-kappaBeta transcription factors to the promoters of their target genes, preventing NF-kappaBeta 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 ( approximately 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-kappaBeta 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-kappaBeta activation in the pathogeneses of occlusive arterial diseases. Our data thus indicate that, by the downregulation of the NF-kappaBeta 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.
authors.affiliation: Department of Cardiac Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
authors.forename: Yu-Jiu
authors.initials: YJ
authors.lastname: Wang
authors.forename: Jin-Tao
authors.initials: JT
authors.lastname: Wang
authors.forename: Quan-Xin
authors.initials: QX
authors.lastname: Fan
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Geng
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003545:Cysteine; D004224:Diterpenes; D019040:E-Selectin; D052002:NF-kappa B p50 Subunit; D013925:Thromboplastin; D019010:Vascular Cell Adhesion Molecule-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C081026:CD68 protein, mouse; C030419:andrographolide