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The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte

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Abstract

Increasing evidence indicates that the anti-malarial agent artemisinin and its derivatives may exert anti-angiogenic effect. In the present study, we explored the effect of artesunate, a artemisinin derivative, on TNFα- and hypoxia-induced expression of hypoxia inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) and inteleukin-8 (IL-8) in human rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further investigated the signal mechanism by which this compound modulates HIF-1α, VEGF and IL-8 expression. RA FLS obtained from patients with active rheumatoid arthritis were pretreated with artesunate, and then stimulated with TNFα and hypoxia. Production of VEGF and IL-8 was measured by ELISA. Nuclear location of HIF-1α was measured by confocal fluorescence microscopy. HIF-1α and other signal transduction proteins expression was measured by Western blot. Artesunate decreased the secretion of VEGF and IL-8 from TNFα- or hypoxia-stimulated RA FLS in a dose-dependent manner. Artesunate also inhibited TNFα- or hypoxia-induced nuclear expression and translocation of HIF-1α. We also showed that artesunate prevented Akt phosphorylation, but did not find evidence that phosphorylation of p38 and ERK was affected. TNFα- or hypoxia-induced secretion of VEGF and IL-8 and expression of HIF-1α were hampered by treatment with the PI3 kinase inhibitor LY294002, suggesting that inhibition of PI3 kinase/Akt activation might inhibit VEGF and IL-8 secretion and HIF-1α expression induced by TNFα or hypoxia. Our results suggest that artesunate inhibits angiogenic factor expression in RA FLS, and provide novel evidence that, as a low-cost agent, artesunate may have therapeutic potential for RA.

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Acknowledgments

The authors would like to thank Ning Luo for her technical assistance. This work is supported in part by grants from National Natural Science Foundation of China (No u0772001), Natural Science Foundation of Guangdong, China (No 07001643), Scientific and Technological Project of Guangdong Province (No 2006B36003014), and Excellent Talent Program of the First Affiliated Hospital, SunYat-sen University, China.

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Authors and Affiliations

  1. Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No 58 Zhongshan Road 2, 510080, Guangzhou, Guangdong, People’s Republic of China

    Ya He, Haobo Lin, Xiuyan Yang, Yujin Ye, Liuqin Liang, Zhongping Zhan & Hanshi Xu

  2. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China

    Jinjin Fan & Xiuqing Dong

  3. Department of Pathology, School of Medicine, Northwestern University, Chicago, IL, USA

    Lin Sun

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  1. Ya He
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  10. Hanshi Xu
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Correspondence to Hanshi Xu.

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Y. He, J. Fan, and H. Lin contributed equally to the study.

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He, Y., Fan, J., Lin, H. et al. The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte. Rheumatol Int 31, 53–60 (2011). https://doi.org/10.1007/s00296-009-1218-7

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