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


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.


Artesunate Angiogenesis Rheumatoid arthritis Signal transduction Fibroblast-like synoviocytes 



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.


  1. 1.
    Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T (2006) Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology 45:669–675CrossRefPubMedGoogle Scholar
  2. 2.
    Peters CL, Morris CJ, Mapp PI, Blake DR, Lewis CE, Winrow VR (2004) The transcription factors hypoxia-inducible factor1 alpha and Ets-1 colocalize in the hypoxic synovium of inflamed joints in adjuvant-induced arthritis. Arthritis Rheum 50:291–296CrossRefPubMedGoogle Scholar
  3. 3.
    Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F (2005) Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis 64:971–980CrossRefPubMedGoogle Scholar
  4. 4.
    Szekanecz Z, Gaspar L, Koch AE (2005) Angiogenesis in rheumatoid arthritis. Front Biosci 10:1739–1753CrossRefPubMedGoogle Scholar
  5. 5.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  6. 6.
    Brown LF, Detmar M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF (1997) Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS 79:233–269PubMedGoogle Scholar
  7. 7.
    Koach AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N (1994) Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 152:4149–4156Google Scholar
  8. 8.
    Fava RA, Olsen NJ, Spencer-Green G et al (1994) Vascular permeability factor/vascular endothelial growth factor: accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346CrossRefPubMedGoogle Scholar
  9. 9.
    Paleolog EM, Fava RA (1998) Angiogenesis in rheumatoid arthritis: implication for future therapeutic strategies. Springer Semin Immunopathol 20:73–94CrossRefPubMedGoogle Scholar
  10. 10.
    Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN (1998) Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor α and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 41:1258–1265CrossRefPubMedGoogle Scholar
  11. 11.
    Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog EM (2000) Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest 80:1195–1205CrossRefPubMedGoogle Scholar
  12. 12.
    Hollander AP, Corke KP, Freemont AJ, Lewis CE (2001) Expression of hypoxia-inducible factor 1 alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum 44:1540–1544CrossRefPubMedGoogle Scholar
  13. 13.
    Giatromanolaki A, Sivridis E, Maltezos E et al (2003) Upregulated hypoxia inducible factor-1 alpha and -2 alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 5:R193–R201CrossRefPubMedGoogle Scholar
  14. 14.
    Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1 alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657CrossRefPubMedGoogle Scholar
  15. 15.
    Meshnick SR, Taylor TE, Kamchonwongpaisan S (1996) Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 60:301–315PubMedGoogle Scholar
  16. 16.
    Haynes RK (2001) Artemisinin and derivatives: the future for malaria treatment? Curr Opin Infect Dis 14:719–726PubMedGoogle Scholar
  17. 17.
    Huan-huan C, Li-li Y, Shang-bin L (2004) Artesunate reduces chicken chorioallantoic membrane neovascularisation and exhibits antiangiogenic and apoptotic activity on human microvascular dermal endothelial cell. Cancer Lett 211:163–173CrossRefPubMedGoogle Scholar
  18. 18.
    Efferth T (2006) Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 7:407–421CrossRefPubMedGoogle Scholar
  19. 19.
    Aldieri E, Atragene D, Bergandi L et al (2003) Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-κB activation. FEBS Lett 552:141–144CrossRefPubMedGoogle Scholar
  20. 20.
    Zhou WL, Wu JM, Wu QL et al (2005) A novel artemisinin derivative, 3-(12-beta-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo. Acta Pharmacol Sin 26:1352–1358CrossRefPubMedGoogle Scholar
  21. 21.
    Lee S (2007) Artemisinin, promising lead natural product for various drug developments. Mini Rev Chem 7:411–422CrossRefGoogle Scholar
  22. 22.
    Wartenberg M, Wolf S, Budde P et al (2003) The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Lab Invest 83:1647–1655CrossRefPubMedGoogle Scholar
  23. 23.
    Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRefPubMedGoogle Scholar
  24. 24.
    Zhou HJ, Wang WQ, Wu GD, Lee J, Li A (2007) Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol 47:131–138CrossRefPubMedGoogle Scholar
  25. 25.
    Dell’Eva R, Pfeffer U, Vené R et al (2004) Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68:2359–2366CrossRefPubMedGoogle Scholar
  26. 26.
    Nagashima M, Wauke K, Hirano D et al (2000) Effects of combinations of anti-rheumatic drugs on the production of vascular endothelial growth factor and basic fibroblast growth in cultured synoviocytes and patients with rheumatoid arthritis. Rheumatology (Oxford) 39:1255–1262CrossRefGoogle Scholar
  27. 27.
    Westra J, Brouwer E, Bos R et al (2007) Regulation of cytokine-induced HIF-1α expression in rheumatoid synovial fibroblasts. Ann NY Acad Sci 1108:340–348CrossRefPubMedGoogle Scholar
  28. 28.
    Paleolog EM (2002) Angiogenesis in rheumatoid arthritis. Arthritis Res 4(suppl 3):S81–S90CrossRefPubMedGoogle Scholar

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

Personalised recommendations