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Rheumatology International

, Volume 31, Issue 1, pp 53–60 | Cite as

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

  • Ya He
  • Jinjin Fan
  • Haobo Lin
  • Xiuyan Yang
  • Yujin Ye
  • Liuqin Liang
  • Zhongping Zhan
  • Xiuqing Dong
  • Lin Sun
  • Hanshi XuEmail author
Original Article

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.

Keywords

Artesunate Angiogenesis Rheumatoid arthritis Signal transduction Fibroblast-like synoviocytes 

Notes

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.

Conflict of interest statement

No conflict of interest has been declared by authors.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ya He
    • 1
  • Jinjin Fan
    • 2
  • Haobo Lin
    • 1
  • Xiuyan Yang
    • 1
  • Yujin Ye
    • 1
  • Liuqin Liang
    • 1
  • Zhongping Zhan
    • 1
  • Xiuqing Dong
    • 2
  • Lin Sun
    • 3
  • Hanshi Xu
    • 1
    Email author
  1. 1.Department of Rheumatology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of Nephrology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  3. 3.Department of Pathology, School of MedicineNorthwestern UniversityChicagoUSA

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