Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts
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To investigate the effect of FK228 on the in vitro expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) by rheumatoid arthritis synovial fibroblasts (RASFs), and on the in vivo expression of VEGF and angiogenesis in the synovial tissue of mice with collagen-antibody-induced arthritis (CAIA).
RASFs were stimulated with IL-1β and TNFα and then incubated under hypoxia (1 % O2) with various concentrations of FK228. The effects of FK228 on the expression of HIF-1α and VEGF mRNA were examined by quantitative real-time PCR. Changes in HIF-1α protein expression and the secretion of VEGF protein into the culture medium were examined by Western blot analysis and ELISA, respectively. Immunohistochemical analysis was carried out to investigate the expression and distribution of VEGF in synovial tissues of CAIA mice.
The cytokine-stimulated expression of HIF-1α and VEGF mRNA was inhibited by FK228 in a dose-dependent manner. FK228 also reduced the expression of HIF-1α and VEGF protein. Intravenous administration of FK228 (2.5 mg/kg) suppressed VEGF expression, and also blocked angiogenesis in the synovial tissue of CAIA.
FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF.
- Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts
Volume 57, Issue 1 , pp 4-10
- Cover Date
- Print ISSN
- Online ISSN
- SP Birkhäuser Verlag Basel
- Additional Links
- Histone deacetylase (HDAC)
- Rheumatoid arthritis
- Vascular endothelial growth factor (VEGF)
- Hypoxia-inducible factor-1 (HIF-1)
- Industry Sectors
- Author Affiliations
- 1. Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University, Okayama, Japan
- 3. Department of Molecular Biology and Biochemistry, Okayama University, Okayama, Japan
- 2. Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
- 4. National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
- 5. Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City, Okayama, 700-8558, Japan