Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts

H. Manabe, Yoshihisa Nasu, T. Komiyama, Takayuki Furumatsu, A. Kitamura, Shinichi Miyazawa, Y. Ninomiya, Toshihumi Ozaki, H. Asahara, Keiichiro Nishida

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Abstract

Objective: 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). Methods: 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. Results: 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. Conclusion: FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF.

Original languageEnglish
Pages (from-to)4-10
Number of pages7
JournalInflammation Research
Volume57
Issue number1
DOIs
Publication statusPublished - Jan 2008

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Histone Deacetylases
Fibroblasts
Vascular Endothelial Growth Factor A
Hypoxia-Inducible Factor 1
Down-Regulation
Experimental Arthritis
Collagen
Tissue
Antibodies
Rheumatoid Arthritis
Hypoxia
Messenger RNA
Proteins
Angiogenesis Inducing Agents
Therapeutic Uses
romidepsin
Interleukin-1
Intravenous Administration
Culture Media
Real-Time Polymerase Chain Reaction

Keywords

  • Histone deacetylase (HDAC)
  • Hypoxia-inducible factor-1 (HIF-1)
  • Rheumatoid arthritis
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology (medical)
  • Immunology
  • Cell Biology

Cite this

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title = "Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts",
abstract = "Objective: 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). Methods: 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. Results: 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. Conclusion: FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF.",
keywords = "Histone deacetylase (HDAC), Hypoxia-inducible factor-1 (HIF-1), Rheumatoid arthritis, Vascular endothelial growth factor (VEGF)",
author = "H. Manabe and Yoshihisa Nasu and T. Komiyama and Takayuki Furumatsu and A. Kitamura and Shinichi Miyazawa and Y. Ninomiya and Toshihumi Ozaki and H. Asahara and Keiichiro Nishida",
year = "2008",
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doi = "10.1007/s00011-007-7036-z",
language = "English",
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T1 - Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts

AU - Manabe, H.

AU - Nasu, Yoshihisa

AU - Komiyama, T.

AU - Furumatsu, Takayuki

AU - Kitamura, A.

AU - Miyazawa, Shinichi

AU - Ninomiya, Y.

AU - Ozaki, Toshihumi

AU - Asahara, H.

AU - Nishida, Keiichiro

PY - 2008/1

Y1 - 2008/1

N2 - Objective: 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). Methods: 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. Results: 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. Conclusion: FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF.

AB - Objective: 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). Methods: 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. Results: 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. Conclusion: FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF.

KW - Histone deacetylase (HDAC)

KW - Hypoxia-inducible factor-1 (HIF-1)

KW - Rheumatoid arthritis

KW - Vascular endothelial growth factor (VEGF)

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