Deng Qiudi, Bai Shutong, Gao Wanjiao, Tong Li
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
Int Immunopharmacol. 2015 Dec;29(2):302-313. doi: 10.1016/j.intimp.2015.11.001. Epub 2015 Nov 6.
Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease. As RA progresses, the hyperplastic synovial pannus creates a hypoxic, inflammatory environment that induces angiogenesis. Further vascularization of the synovial tissue promotes pannus growth and continued infiltration of inflammatory leukocytes, thus perpetuating the disease. Pristimerin inhibits inflammation and tumor angiogenesis. The present study focused on the inhibition of angiogenesis by Pristimerin in adjuvant-induced arthritic rats and the underlying molecular mechanisms. Our results clearly demonstrate for the first time that Pristimerin significantly reduces vessel density in synovial membrane tissues of inflamed joints and reduces the expression of pro-angiogenic factors in sera, including TNF-α, Ang-1, and MMP-9. Pristimerin also decreased the expression of VEGF and p-VEGFR2 in the synovial membrane, whereas the total amount of VEGFR2 remained unchanged. Pristimerin suppressed the sprouting vessels of the aortic ring and inhibited VEGF-induced HFLS-RA migration in vitro. Pristimerin also inhibited VEGF-induced proliferation, migration and tube formation by HUVECs, blocked the autophosphorylation of VEGF-induced VEGFR2 and consequently downregulated the signaling pathways of activated PI3K, AKT, mTOR, ERK1/2, JNK, and p38 in VEGF-induced HUVECs. Our results indicate that Pristimerin suppressed synovial angiogenesis in our rat model and in vitro by interrupting the targeting of VEGFR2 activation. Therefore, Pristimerin has potential as an angiogenesis inhibitor in the treatment of rheumatoid arthritis.
类风湿性关节炎（RA）是一种进行性炎症性自身免疫疾病。随着RA的进展，增生性滑膜血管翳会形成低氧、炎症环境，从而诱导血管生成。滑膜组织的进一步血管化促进血管翳生长和炎症白细胞持续浸润，进而使疾病持续存在。扁蒴藤素可抑制炎症和肿瘤血管生成。本研究聚焦于扁蒴藤素对佐剂诱导性关节炎大鼠血管生成的抑制作用及其潜在分子机制。我们的结果首次清楚地表明，扁蒴藤素可显著降低炎症关节滑膜组织中的血管密度，并降低血清中促血管生成因子的表达，包括肿瘤坏死因子-α（TNF-α）、血管生成素-1（Ang-1）和基质金属蛋白酶-9（MMP-9）。扁蒴藤素还可降低滑膜中血管内皮生长因子（VEGF）和磷酸化血管内皮生长因子受体2（p-VEGFR2）的表达，而血管内皮生长因子受体2（VEGFR2）的总量保持不变。扁蒴藤素可抑制主动脉环的血管芽生，并在体外抑制VEGF诱导的人成纤维样滑膜细胞（HFLS-RA）迁移。扁蒴藤素还可抑制VEGF诱导的人脐静脉内皮细胞（HUVECs）增殖、迁移和管腔形成，阻断VEGF诱导的VEGFR2自磷酸化，从而下调VEGF诱导的HUVECs中活化的磷脂酰肌醇-3激酶（PI3K）、蛋白激酶B（AKT）、哺乳动物雷帕霉素靶蛋白（mTOR）、细胞外信号调节激酶1/2（ERK1/2）、应激活化蛋白激酶（JNK）和p38的信号通路。我们的结果表明，扁蒴藤素通过阻断VEGFR2激活靶点，在我们的大鼠模型和体外抑制滑膜血管生成。因此，扁蒴藤素在类风湿性关节炎治疗中具有作为血管生成抑制剂的潜力。
