Journal of Physiology & Pathology in Korean Medicine (동의생리병리학회지)

The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine (대한동의생리학회·한의병리학회)
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Effects of Heme Oxygenase-1 on VEGF Expression in Rheumatoid Arthritis

류마티스 관절염에서 HO-1에 의한 VEGF 발현 유도에 대한 연구

  • Lee, Seung-Hoon (Department of Pathology, School of Medicine, Pennsylvania University) ;
  • Kwan, Sang-Chul (Department of Anatomy, School of Medicine, Wonkwang University) ;
  • Byun, Seung-Jae (Department of General Surgery, School of Medicine, Wonkwang University) ;
  • Jang, Sung-Jo (Department of Neuro-Surgery, School of Medicine, Wonkwang University)
  • 이승훈 (펜실베이니아대학교 의과대학 병리학교실) ;
  • 권상철 (원광대학교 의과대학 해부학교실) ;
  • 변승재 (원광대학교 의과대학 일반외과학교실) ;
  • 장성조 (원광대학교 의과대학 신경외과학교실)
  • Published : 2008.08.25
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Abstract

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to various stresses and mediators of inflammation. HO-1 has been recently implicated in regulation of angiogenesis via expression of VEGF. The purpose of this study was to determine the effects of HO-1 modulation on the collagen-induced arthritis (CIA) model and on angiogenesis via up- regulation of VEGF expression in human synovial fibroblast. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 1 to day 35 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, histopathologic changes were examined on the joints. VEGF expression in paws were measured by immunohistochemical stain. mRNA expression of HO-1 and VEGF stimulated with various concentration of $TNF-{\alpha}$, CoPP accessed on human synovial fibroblast by RT-PCR. Effects of pretreatment with SnPP on mRNA expression of HO-1 and VEGF in the presence of CoPP and $TNF-{\alpha}$ in synovial fibroblast was accessed by Real-time RT-PCR. Administration of cobalt protoporphyrin IX significantly induced the inflammatory response, with increased arthritis index and expression of VEGF in the paws of the arthritis models. Treatment with SnPP significantly reduced the severity of CIA through inhibition of joint inflammation and cartilage destruction. The expression of VEGF were also significantly reduced by SnPP treatment in the paw. CoPPIX as inducer of HO-1, increased HO-1 and VEGF expression dose dependently in synovial fibroblast. In contrast, inhibition of HO-1 activity by SnPPIX abrogated CoPPIX-induced HO-1 and VEGF production in synovial fibroblast. Stimulation with $TNF-{\alpha}$ increased HO-1 and VEGF expression itself and showed additive effect on HO-1 and VEGF expression when it treated with CoPP. When SnPP was treated with CoPP and $TNF-{\alpha}$, it abrogated the CoPP induced HO-1 and VEGF expression and also abrogated $TNF-{\alpha}$ induced HO-1 and VEGF expression in synovial fibroblast. The effects of HO-1 induction in rheumatoid arthritis results in aggravation of arthritis via up-regulation of VEGF. I concluded that inhibition of the expression or activity of HO-1 could be a therapeutic target of rheumatoid arthritis.

Keywords

References

  1. Koch, A.E. angiogenesis implication for rheumatoid arthritis. Arthritis and Rheumatism 41: 951-962, 1998 https://doi.org/10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D
  2. Stuart, J.M., Townes, A.S., Kang, A.H. The role of collagen autoimmunity in animal models and human diseases. J Invest Dermatol 1: 121-127, 1982
  3. Maines, M.D. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37: 517-554, 1997 https://doi.org/10.1146/annurev.pharmtox.37.1.517
  4. Otterbein, L.E., Choi, A.M. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279: 1029-1037, 2000 https://doi.org/10.1152/ajplung.2000.279.6.L1029
  5. Takeda, Y., Takeno, M., Lwasaki, M., Kobayashi, H., Kirino, Y., Ueda, A. et al. Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-ds DNA antibody. Clin Exp Immunol 138: 237-244, 2004 https://doi.org/10.1111/j.1365-2249.2004.02594.x
  6. Oterbein, L.E., Kolls, J.K., Mantell, L.L., cook, J.L., Alam, J., Choi, A.M. Exogenous administration of heme-oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Cli invest 103: 1047-1054, 1999 https://doi.org/10.1172/JCI5342
  7. Ishikawa, K., Sugawara, D., Wang, X., Suzuki Itabe, H. et al. Heme oxygenase-1 inhibits artherosclerotic lesion formation in Idl-receptor knockout mice. Circ Res 88: 506-512, 2001 https://doi.org/10.1161/01.RES.88.5.506
  8. Isabel, Devesa, I., Ferrandiz, M.L., Guillen, I., Cerda, J.M., Alcaraz, M.J. Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis. Lab Invest. 2005
  9. Devesa, I., Ferrandiz, M.L., Terencio, M.C., Joosten, L.A. Influence of heme oxygenase 1 modulation on the progression of murine collagen-induced arthritis. Arthritis Rheum. 52(10):3230-3238, 2005 https://doi.org/10.1002/art.21356
  10. Cha, H.S., Ahn, K.S., Jeon, C.H., Kim, J., Song, Y.W., Koh, E.M. Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts. Clin Exp Rheumatol 21: 593-598, 2003
  11. Jackson, J.R., Minton, J.A., Ho, M.L., Wei, N., winkler, J.D. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatology 24: 1253-1259, 1997
  12. Fava, R.A., Olsen, N.J., Spencer-Green, G., Yeo, T.K. berse, B. et al. Vascular permeability factor/endothelial growth factor(VPF/VEGF):accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180: 341-346, 1994 https://doi.org/10.1084/jem.180.1.341
  13. Jazwa, A., Loboda, A., Golda, S., Cisowski, J., Szelag, M., Zagorska, A., Sroczynska, P., Drukala, L. Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes. Free Radic Biol Med. 40(7):1250-1263, 2006 https://doi.org/10.1016/j.freeradbiomed.2005.11.016
  14. Loboda, A., Jazwa, B., Wegiel, A., Jozkowicz, J. Heme oxygenase-1-dependent and -independent regulation of angiogenic genes expression: effect of cobalt protoporphyrin and cobalt chloride on VEGF and IL-8 synthesis in human microvascular endothelial cells. Cell Mol Biol (Noisy-le-grand). 51(4):347-355, 2005
  15. Alcarez, M.J., Fernandez, P., Guillen, M.I. Anti- inflammatory actions of the heme oxygenase-1 pathway. Curr Pharm Des 9(30):2541-2551, 2003 https://doi.org/10.2174/1381612033453749
  16. Zwerina, J., Tzima, S., Hayer, S., Redlich, K., Hoffmann, O. : Heme-oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. FASEB J. 19(14):2011-2013, 2005 https://doi.org/10.1096/fj.05-4278fje
  17. 장성조, 김유림, 최은영, 오재민, 권덕수. 콜라겐 유도 관절염 모델에서 HO-1의 역할에 관한 연구. 대한해부학회지 39(5):393-399, 2006
  18. Clavel, G., Bessis, N., Boissier, M.C. Recent data on the role for angiogenesis in rheumatoid arthritis. Joint Bone Spine 70: 321-326, 2003 https://doi.org/10.1016/S1297-319X(03)00088-5
  19. De Bandt, M., Ben Mahdi, M.H., Ollivier, V. et al. Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis. J Immunol 171: 4853-4859, 2003 https://doi.org/10.4049/jimmunol.171.9.4853
  20. Dulak, J., Jozkowicz, A., Foresti, R. et al. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal 4: 229-240, 2002 https://doi.org/10.1089/152308602753666280
  21. Jozkowicz, A., huk, I., Nigisch, A., Weigel, G., Dulak, J. Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1. Antioxid Redox Signal. 4(4):577-585, 2002 https://doi.org/10.1089/15230860260220076
  22. Cha, H.S., Bae, E.K., Koh, J.H., Chai, J.Y., Jeon, C.H., Ahn, C.H., Koh, E.M. Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes. J Rheumatol. 34(1):16-19, 2007
  23. Cha, H.S., Ahn, K.S., Jeon, C.H., Kim, J., Song, Y.W., Koh, E.M. Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts. Clin Exp Rheumatol 21: 593-598, 2003