Department of Pharmacology of Chinese Materia Medica, State Key Laboratory of Natural Medicines.
Exp Biol Med (Maywood). 2012 Aug;237(8):919-32. doi: 10.1258/ebm.2012.011416. Epub 2012 Aug 8.
Synovial angiogenesis is well recognized as participating in the pathogenesis of rheumatoid arthritis (RA) and has been regarded as a potential target for RA therapy. Previously, we have shown that norisoboldine (NOR) can protect joints from destruction in mice with collagen II-induced arthritis (CIA). Here, we investigate the effect of NOR on synovial angiogenesis in adjuvant-induced arthritis (AA) rats, and clarify the mechanisms in vitro. NOR, administered orally, significantly reduced the number of blood vessels and expression of growth factors in the synovium of AA rats. In vitro, it markedly prevented the migration and sprouting of endothelial cells. Notably, the endothelial tip cell phenotype, which is essential for the migration of endothelial cells and subsequent angiogenesis, was significantly inhibited by NOR. This inhibitory effect was attenuated by pretreatment with N-{N-[2-(3,5-difluorophenyl) acetyl]-(S)-alanyl}-(S)-phenylglycine tert-butyl ester, a Notch1 inhibitor, suggesting that the action of NOR was related to the Notch1 pathway. A molecular docking study further confirmed that NOR was able to promote Notch1 activation by binding the Notch1 transcription complex. In conclusion, NOR was able to prevent synovial angiogenesis in AA rats, which is a putatively new mechanism responsible for its anti-rheumatoid effect. The anti-angiogenesis action of NOR was likely achieved by moderating the Notch1 pathway-related endothelial tip cell phenotype with a potential action target of the Notch1 transcription complex.
滑膜血管生成被认为参与类风湿关节炎（RA）的发病机制，已被视为 RA 治疗的潜在靶点。先前，我们已经表明，去甲异波尔定（NOR）可以保护 II 型胶原诱导的关节炎（CIA）小鼠的关节免受破坏。在这里，我们研究了 NOR 对佐剂诱导关节炎（AA）大鼠滑膜血管生成的影响，并阐明了其体外机制。NOR 通过口服给药，可显著减少 AA 大鼠滑膜中血管数量和生长因子的表达。在体外，它明显阻止了内皮细胞的迁移和发芽。值得注意的是，内皮尖端细胞表型对于内皮细胞的迁移和随后的血管生成是必不可少的，而 NOR 显著抑制了这种表型。用 Notch1 抑制剂 N-[[2-(3,5-二氟苯基)乙酰基]-(S)-丙氨酰基]-(S)-苯甘氨酸叔丁酯预处理可减弱这种抑制作用，表明 NOR 的作用与 Notch1 途径有关。分子对接研究进一步证实，NOR 通过结合 Notch1 转录复合物，能够促进 Notch1 的激活。总之，NOR 能够防止 AA 大鼠滑膜血管生成，这可能是其抗风湿作用的新机制。NOR 的抗血管生成作用可能是通过调节 Notch1 途径相关的内皮尖端细胞表型来实现的，其潜在的作用靶点是 Notch1 转录复合物。
