Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade.
Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade.
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雷公藤内酯醇通过靶向血管生成级联在类风湿性关节炎中发挥抗血管生成作用。
DOI：
10.1371/journal.pone.0077513
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lin N
中科院分区：
文献类型：
--
作者：
Kong X;Zhang Y;Liu C;Guo W;Li X;Su X;Wan H;Sun Y;Lin N
类风湿关节炎（RA）的特点是血管前严重炎症期，随后是血管生长高度增加的血管期。由于血管生成被认为是维持炎症和免疫反应的必要事件，以及支持RA的包膜生长和发展，抑制血管生成已被提出作为RA的一种新的治疗策略。雷公藤甲素是一种来自雷公藤的三氧化二萜，已被广泛用于治疗RA患者。它还在几种癌症类型中作为肿瘤血管生成的小分子抑制剂。然而，雷公藤甲素是否具有抗RA血管生成作用尚不清楚。为了解决这一问题，我们采用注射牛ⅱ型胶原构建DA大鼠胶原诱导关节炎（CIA）模型。然后，CIA大鼠在第一次免疫后第1天开始给予雷公藤甲素（11-45µg/kg/天）。与对照CIA大鼠相比，雷公藤甲素处理CIA大鼠关节炎评分（P<0.05）和炎症关节关节炎发生率（P<0.05）均显著降低。更有趣的是，11 ~ 45µg/kg雷公藤甲素可以显著降低炎症关节滑膜组织的毛细血管和小、中、大血管密度（均P<0.05）。此外，雷公藤甲素抑制基质诱导的HFLS-RA和HUVEC细胞粘附。它还破坏了基质上HUVEC的管状形成，并分别抑制了vegf诱导的HFLS-RA和HUVEC的趋化迁移。此外，雷公雷甲素显著降低TNF-α、IL-17、VEGF、VEGFR、Ang-1、Ang-2和Tie2等血管生成激活因子的表达，并在蛋白水平上抑制il -β诱导的ERK、p38和JNK磷酸化。总之，我们的数据首次表明雷公藤甲素可能通过下调血管生成激活因子和抑制丝裂原激活的蛋白激酶下游信号通路的激活，在RA体内和体外检测系统中具有抗血管生成作用。
Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA) model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11–45 µg/kg/day) starting on the day 1 after first immunization. The arthritis scores (P<0.05) and the arthritis incidence (P<0.05) of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11∼45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05). Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS–RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS–RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway.
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