Molecules and Cells

, Volume 33, Issue 6, pp 563–574 | Cite as

Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ

  • Deokbum Park
  • Youngmi Kim
  • Hyunah Kim
  • Kyungjong Kim
  • Yun-Sil Lee
  • Jongseon Choe
  • Jang-Hee Hahn
  • Hansoo Lee
  • Jongwook Jeon
  • Chulhee Choi
  • Young-Myeong Kim
  • Dooil JeoungEmail author
Research Article


Hyaluronic acid (HA) has been shown to promote angiogenesis. However, the mechanism behind this effect remains largely unknown. Therefore, in this study, the mechanism of HA-induced angiogenesis was examined. CD44 and PKCδ were shown to be necessary for induction of the receptor for HA-mediated cell motility (RHAMM), a HA-binding protein. RHAMM was necessary for HA-promoted cellular invasion and endothelial cell tube formation. Cytokine arrays showed that HA induced the expression of plasminogen activator-inhibitor-1 (PAI), a downstream target of TGFβ receptor signaling. The induction of PAI-1 was dependent on CD44 and PKCδ. HA also induced an interaction between RHAMM and TGFβ receptor I, and induction of PAI-1 was dependent on RHAMM and TGFβ receptor I. Histone deacetylase 3 (HDAC3), which is decreased by HA via rac1, reduced induction of plasminogen activator inhibitor-1 (PAI-1) by HA. ERK, which interacts with RHAMM, was necessary for induction of PAI-1 by HA. Snail, a downstream target of TGFβ signaling, was also necessary for induction of PAI-1. The down regulation of PAI-1 prevented HA from enhancing endothelial cell tube formation and from inducing expression of angiogenic factors, such as ICAM-1, VCAM-1 and MMP-2. HDAC3 also exerted reduced expression of MMP-2. In this study, we provide a novel mechanism of HA-promoted angiogenesis, which involved RHAMM-TGFβRI signaling necessary for induction of PAI-1.


CD44 hyaluronic acid PAI-1 RHAMM TGFβ signaling 


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  1. Adenuga, D., Yao, H., March, T.H., Seagrave, J., and Rahman, I. (2009). Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am. J. Respir. Cell Mol. Biol. 40, 464–473.PubMedCrossRefGoogle Scholar
  2. Bajou, K., Peng, H., Laug, W.E., Maillard, C., Noel, A., Foidart, J.M., Martial, J.A., and DeClerck, Y.A. (2008). Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14, 324–334.PubMedCrossRefGoogle Scholar
  3. Barter, M.J., Pybus, L., Litherland, G.J., Rowan, A.D., Clark, I.M., Edwards, D.R., Cawston, T.E., and Young, D.A. (2010). HDACmediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes. Matrix Biol. 29, 602–612.PubMedCrossRefGoogle Scholar
  4. Basu, A., Menicucci, G., Maestas, J., Das, A., and McGuire, P. (2009). Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 50, 4974–4981.PubMedCrossRefGoogle Scholar
  5. Bendinelli, P., Matteucci, E., Maroni, P., and Desiderio, M.A. (2009). NF-kappaB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells. Mol. Cancer Res. 8, 1328–1341.CrossRefGoogle Scholar
  6. Bhaskara, S., Chyla, B.J., Amann, J.M., Knutson, S.K., Cortez, D., Sun, Z.W., and Hiebert, S.W. (2008). Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 30, 61–72.PubMedCrossRefGoogle Scholar
  7. Bhaskara, S., Knutson, S.K., Jiang, G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Yuan, J.L., Bonine-Summers, A.R., et al. (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447.PubMedCrossRefGoogle Scholar
  8. Boosani, C.S., Nalabothula, N., Sheibani, N., and Sudhakar, A. (2010). Inhibitory effects of arresten on bFGF-induced proliferation, migration, and matrix metalloproteinase-2 activation in mouse retinal endothelial cells. Curr. Eye Res. 35, 45–55.PubMedCrossRefGoogle Scholar
  9. Bourguignon, L.Y., Gilad, E., Peyrollier, K., Brightman, A., and Swanson, R.A. (2007). Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes. J. Neurochem. 101, 1002–1017.PubMedCrossRefGoogle Scholar
  10. Cavallo-Medved, D., Rudy, D., Blum, G., Bogyo, M., Caglic, D., and Sloane, B.F. (2009). Live-cell imaging demonstrates extracellular matrix degradation in association with active cathepsin B in caveolae of endothelial cells during tube formation. Exp. Cell Res. 315, 1234–1246.PubMedCrossRefGoogle Scholar
  11. Chetty, C., Lakka, S.S., Bhoopathi, P., and Rao, J.S. (2010). MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int. J. Cancer 127, 1081–1095.PubMedCrossRefGoogle Scholar
  12. Cho, H.J., Kang, J.H., Jeong, J.H., Jeong, Y.J., Park, K.K., Park, Y.Y., Moon, Y.S., Kim, H.T., Chung, I.K., Kim, C.H., et al. (2012). Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells. Mol. Biol. Rep. 39, 4597–4603.PubMedCrossRefGoogle Scholar
  13. Contreras, E.G., Gaete, M., Sánchez, N., Carrasco, H., and Larraín, J. (2009). Early requirement of Hyaluronan for tail regeneration in Xenopus tadpoles. Development 136, 2987–2996.PubMedCrossRefGoogle Scholar
  14. Craig, E.A., Parker, P., and Camenisch, T.D. (2009). Size-dependent regulation of Snail2 by hyaluronan: its role in cellular invasion. Glycobiology 19, 890–898.PubMedCrossRefGoogle Scholar
  15. Dai, J., Peng, L., Fan, K., Wang, H., Wei, R., Ji, G., Cai, J., Lu, B., Li, B., Zhang, D., et al. (2009). Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells. Oncogene 28, 3412–3422.PubMedCrossRefGoogle Scholar
  16. Diebold, I., Djordjevic, T., Petry, A., Hatzelmann, A., Tenor, H., Hess, J., and Görlach, A. (2009). Phosphodiesterase 2 mediates redox-sensitive endothelial cell proliferation and angiogenesis by thrombin via Rac1 and NADPH oxidase. Circ. Res. 104, 1169–1177.PubMedCrossRefGoogle Scholar
  17. Evert, B.O., Araujo, J., Vieira-Saecker, A.M., de Vos, R.A., Harendza, S., Klockgether, T., and Wüllner, U. (2006). Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J. Neurosci. 26, 11474–11486.PubMedCrossRefGoogle Scholar
  18. Fabre-Guillevin, E., Malo, M., Cartier-Michaud, A., Peinado, H., Moreno-Bueno, G., Vallée, B., Lawrence, D.A., Palacios, J., Cano, A., Barlovatz-Meimon, G., et al. (2008). PAI-1 and functional blockade of SNAI1 in breast cancer cell migration. Breast Cancer Res. 10, R100.PubMedCrossRefGoogle Scholar
  19. Fischle, W., Dequiedt, F., Hendzel, M.J., Guenther, M.G., Lazar, M.A., Voelter, W., and Verdin, E. (2002). Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57.PubMedCrossRefGoogle Scholar
  20. Gao, S., Nielsen, B.S., Krogdahl, A., Sørensen, J.A., Tagesen, J., Dabelsteen, S., Dabelsteen, E., and Andreasen, P.A. (2010). Epigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa. Genes Chromosomes Cancer 49, 526–538.PubMedGoogle Scholar
  21. Garrett, T.A., Van Buul, J.D., and Burridge, K. (2007). VEGFinduced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp. Cell Res. 313, 3285–3297.PubMedCrossRefGoogle Scholar
  22. Golshani, R., Lopez, L., Estrella, V., Kramer, M., Iida, N., and Lokeshwar, V.B. (2008). Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44. Cancer Res. 68, 483–491.PubMedCrossRefGoogle Scholar
  23. Ha, C.H., Wang, W., Jhun, B.S., Wong, C., Hausser, A., Pfizenmaier, K., McKinsey, T.A., Olson, E.N., and Jin, Z.G. (2008). Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. J. Biol. Chem. 283, 14590–14599.PubMedCrossRefGoogle Scholar
  24. Ha, C.H., Jhun, B.S., Kao, H.Y., and Jin, Z.G. (2008). VEGF stimulates HDAC7 phosphorylation and cytoplasmic accumu-lation modulating matrix metalloproteinase expression and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 28, 1782–1788.PubMedCrossRefGoogle Scholar
  25. Hamilton, S.R., Fard, S.F., Paiwand, F.F., Tolg, C., Veiseh, M., Wang, C., McCarthy, J.B., Bissell, M.J., Koropatnick, J., and Turley, E.A. (2007). The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J. Biol. Chem. 282, 16667–16680.PubMedCrossRefGoogle Scholar
  26. Hasegawa, H., Senga, T., Ito, S., Iwamoto, T., and Hamaguchi, M. (2009). A role for AP-1 in matrix metalloproteinase production and invadopodia formation of v-Crk-transformed cells. Exp. Cell Res. 315, 1384–1392.PubMedCrossRefGoogle Scholar
  27. Hirota, K., and Semenza, G.L. (2001). Rac1 activity is required for the activation of hypoxia-inducible factor 1. J. Biol. Chem. 276, 21166–21172.PubMedCrossRefGoogle Scholar
  28. Itano, N., Sawai, T., Yoshida, M., Lenas, P., Yamada, Y., Imagawa, M., Shinomura, T., Hamaguchi, M., Yoshida, Y., Ohnuki, Y., et al. (1999). Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J. Biol. Chem. 274, 25085–25092.PubMedCrossRefGoogle Scholar
  29. Jayne, S., Zwartjes, C.G., van Schaik, F.M., and Timmers, H.T. (2006). Involvement of the SMRT/NCoR-HDAC3 complex in transcriptional repression by the CNOT2 subunit of the human Ccr4-Not complex. Biochem. J. 398, 461–467.PubMedCrossRefGoogle Scholar
  30. Kim, M.S., Kwon, H.J., Lee, Y.M., Baek, J.H., Jang, J.E., Lee, S.W., Moon, E.J., Kim, H.S., Lee, S.K., Chung, H.Y., et al. (2001). Histone deacetylases induce angiogenesis by negative regula-tion of tumor suppressor genes. Nat. Med. 7, 437–443.PubMedCrossRefGoogle Scholar
  31. Kim, Y., Lee, Y.S., Hahn, J.H., Choe, J., Kwon, H.J., Ro, J.Y., and Jeoung, D. (2008). Hyaluronic acid targets CD44 and inhibits FcepsilonRI signaling involving PKCdelta, Rac1, ROS, and MAPK to exert anti-allergic effect. Mol. Immunol. 45, 2537–2547.PubMedCrossRefGoogle Scholar
  32. Kim, Y., Lee, Y.S., Choe, J., Lee, H., Kim, Y.M., and Jeoung, D. (2008). CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. J. Biol. Chem. 283, 22513–22528.PubMedCrossRefGoogle Scholar
  33. Knutson, S.K., Chyla, B.J., Amann, J.M., Bhaskara, S., Huppert, S.S., and Hiebert, S.W. (2008). Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks, EMBO J. 27, 1017–1028.PubMedCrossRefGoogle Scholar
  34. Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., and Miyazono, K. (2008). Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cellderived endothelial cells. J. Cell Sci. 121, 3317–3324.PubMedCrossRefGoogle Scholar
  35. Koyama, H., Hibi, T., Isogai, Z., Yoneda, M., Fujimori, M., Amano, J., Kawakubo, M., Kannagi, R., Kimata, K., Taniguchi, S., et al. (2007). Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. Am. J. Pathol. 170, 1086–1099.PubMedCrossRefGoogle Scholar
  36. Lee, S.H., Kunz, J., Lin, S.H., and Yu-Lee, L.Y. (2007). 16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway. Cancer Res. 67, 11045–11053.PubMedCrossRefGoogle Scholar
  37. Lin, M.T., Kuo, I.H., Chang, C.C., Chu, C.Y., Chen, H.Y., Lin, B.R., Sureshbabu, M., Shih, H.J., and Kuo, M.L. (2008). Involvement of hypoxia-inducing factor-1alpha-dependent plasminogen activator inhibitor-1 up-regulation in Cyr61/CCN1-induced gastric cancer cell invasion. J. Biol. Chem. 283, 15807–15815.PubMedCrossRefGoogle Scholar
  38. Liu, L.T., Chang, H.C., Chiang, L.C., and Hung, W.C. (2003). Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res. 63, 3069–3072.PubMedGoogle Scholar
  39. Liu, R.M., Choi, J., Wu, J.H., Gaston Pravia, K.A., Lewis, K.M., Brand, J.D., Mochel, N.S., Krzywanski, D.M., Lambeth, J.D., Hagood, J.S., et al. (2010). Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J. Biol. Chem. 285, 16239–16247.PubMedCrossRefGoogle Scholar
  40. Marquez-Aguirre, A., Sandoval-Rodriguez, A., Gonzalez-Cuevas, J., Bueno-Topete, M., Navarro-Partida, J., Arellano-Olivera, I., Lucano-Landeros, S., and Armendariz-Borunda, J. (2009). Adenoviral delivery of dominant-negative transforming growth factor beta type II receptor up-regulates transcriptional repressor SKIlike oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats. J. Gene Med. 1, 207–219.CrossRefGoogle Scholar
  41. Matou-Nasri, S., Gaffney, J., Kumar, S., and Slevin, M. (2009). Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signaling pathways involving Cdc2 and gamma-adducin. Int. J. Oncol. 35, 761–773.PubMedGoogle Scholar
  42. McDonald, J.A., and Camenisch, T.D. (2003). Hyaluronan: Genetic insights into the complex biology of a simple polysaccharide. Glyconjugate J. 19, 331–339.CrossRefGoogle Scholar
  43. McKee, C.M., Lowenstein, C.J., Horton, M.R., Wu, J., Bao, C., Chin, B.Y., Choi, A.M., and Noble, P.W. (1997). Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism. J. Biol. Chem. 272, 8013–8018.PubMedCrossRefGoogle Scholar
  44. Meissner, M., Michailidou, D., Stein, M., Hrgovic, I., Kaufmann, R., and Gille, J. (2009). Inhibition of Rac1 GTPase downregulates vascular endothelial growth factor receptor-2 expression by suppressing Sp1-dependent DNA binding in human endothelial cells. Exp. Dermatol. 18, 863–869.PubMedCrossRefGoogle Scholar
  45. Min, J.K., Cho, Y.L., Choi, J.H., Kim, Y., Kim, J.H., Yu, Y.S., Rho, J., Mochizuki, N., Kim, Y.M., Oh, G.T., et al. (2007). Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice. Blood 109, 1495–1502.PubMedCrossRefGoogle Scholar
  46. Montgomery, R.L., Davis, C.A., Potthoff, M.J., Haberland, M., Fielitz, J., Qi, X., Hill, J.A., Richardson, J.A., and Olson, E.N. (2007). Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21, 1790–1802.PubMedCrossRefGoogle Scholar
  47. Mottet, D., Bellahcène, A., Pirotte, S., Waltregny, D., Deroanne, C., Lamour, V., Lidereau, R., and Castronovo, V. (2007). Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res. 101, 1237–1246.PubMedCrossRefGoogle Scholar
  48. Nedvetzki, S., Gonen, E., Assayag, N., Reich, R., Williams, R.O., Thurmond, R.L., Huang, J.F., Neudecker, B.A., Wang, F.S., Turley, E.A., et al. (2004). RHAMM, a receptor for hyaluronanmediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy. Proc. Natl. Acad. Sci. USA 101, 18081–18086.PubMedCrossRefGoogle Scholar
  49. Osoata, G.O., Yamamura, S., Ito, M., Vuppusetty, C., Adcock, I.M., Barnes, P.J., and Ito, K. (2009). Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem. Biophys. Res. Commun. 384, 366–371.PubMedCrossRefGoogle Scholar
  50. Park, H.J., Kim, S.R., Bae, S.K., Choi, Y.K., Bae, Y.H., Kim, E.C., Kim, W.J., Jang, H.O., Yun, I., Kim, Y.M., et al. (2009). Neuromedin B induces angiogenesis via activation of ERK and Akt in endothelial cells. Exp. Cell Res. 315, 3359–3369.PubMedCrossRefGoogle Scholar
  51. Patel, N., Sundaram, N., Yang, M., Madigan, C., Kalra, V.K., and Malik, P. (2010). Placenta growth factor (PlGF), a novel inducer of plasminogen activator inhibitor-1 (PAI-1) in sickle cell disease (SCD). J. Biol. Chem. 285, 16713–16722.PubMedCrossRefGoogle Scholar
  52. Paugh, B.S., Paugh, S.W., Bryan, L., Kapitonov, D., Wilczynska, K.M., Gopalan, S.M., Rokita, H., Milstien, S., Spiegel, S., and Kordula, T. (2008). EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells. FASEB J. 22, 455–465.PubMedCrossRefGoogle Scholar
  53. Peinado, H., Ballestar, E., Esteller, M., and Cano, A. (2004). Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell. Biol. 24, 306–319.PubMedCrossRefGoogle Scholar
  54. Rössig, L., Li, H., Fisslthaler, B., Urbich, C., Fleming, I., Förstermann, U., Zeiher, A.M., and Dimmeler, S. (2002). Inhibitors of histone deacetylation downregulate the expression of endo-thelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis. Circ. Res. 91, 837–844.PubMedCrossRefGoogle Scholar
  55. Samuel, S.K., Hurta, R.A., Spearman, M.A., Wright, J.A., Turley, E.A., and Greenberg, A.H. (1993). TGF-beta 1 stimulation of cell locomotion utilizes the hyaluronan receptor RHAMM and hyaluronan. J. Cell Biol. 123, 749–758.PubMedCrossRefGoogle Scholar
  56. Sankar, N., Baluchamy, S., Kadeppagari, R.K., Singhal, G., Weitzman, S., and Thimmapaya, B. (2008). p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc. Oncogene 27, 5717–5728.PubMedCrossRefGoogle Scholar
  57. Savani, R.C., Cao, G., Pooler, P.M., Zaman, A., Zhou, Z., and De-Lisser, H.M. (2001). Differential involvement of the hyaluro-nan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J. Biol. Chem. 276, 36770–36778.PubMedCrossRefGoogle Scholar
  58. Sohr, S., and Engeland, K. (2008). RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle 7, 3448–3460.PubMedCrossRefGoogle Scholar
  59. Tabata, T., Kokura, K., Ten Dijke, P., and Ishii, S. (2009). Ski corepressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5. Genes Cells 14, 17–28.PubMedCrossRefGoogle Scholar
  60. Takahashi, E., Nagano, O., Ishimoto, T., Yae, T., Suzuki, Y., Shinoda, T., Nakamura, S., Niwa, S., Ikeda, S., Koga, H., et al. (2010). Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. J. Biol. Chem. 285, 4060–4073.PubMedCrossRefGoogle Scholar
  61. Togi, S., Kamitani, S., Kawakami, S., Ikeda, O., Muromoto, R., Nanbo, A., and Matsuda, T. (2009). HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A. Biochem. Biophys. Res. Commun. 379, 616–620.PubMedCrossRefGoogle Scholar
  62. Tolg, C., Hamilton, S.R., Nakrieko, K.A., Kooshesh, F., Walton, P., McCarthy, J.B., Bissell, M.J., and Turley, E.A. (2006). Rhamm-/-fibroblasts are defective in CD44-mediated ERK1,2 mitogenic signaling, leading to defective skin wound repair. J. Cell Biol. 175, 1017–1028.PubMedCrossRefGoogle Scholar
  63. Urbich, C., Rössig, L., Kaluza, D., Potente, M., Boeckel, J.N., Knau, A., Diehl, F., Geng, J.G., Hoffmann, W.K., Zeiher, A.M., et al. (2009). HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells. Blood 113, 5669–5679.PubMedCrossRefGoogle Scholar
  64. Ushio-Fukai, M., Tang, Y., Fukai, T., Dikalov, S.I., Ma, Y., Fujimoto, M., Quinn, M.T., Pagano, P.J., Johnson, C., and Alexander, R.W. (2002). Novel role of gp91 (phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ. Res. 91, 1160–1167.PubMedCrossRefGoogle Scholar
  65. Villagra, A., Ulloa, N., Zhang, X., Yuan, Z., Sotomayor, E., and Seto, E. (2007). Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression. J. Biol. Chem. 282, 35457–35470.PubMedCrossRefGoogle Scholar
  66. von Burstin, J., Eser, S., Paul, M.C., Seidler, B., Brandl, M., Messer, M., von Werder, A., Schmidt, A., Mages, J., Pagel, P., et al. (2009). E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 137, 361–371.CrossRefGoogle Scholar
  67. Wang, C., Thor, A.D., Moore, D.H. 2nd, Zhao, Y., Kerschmann, R., Stern, R., Watson, P.H., and Turley, E.A. (1998). The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogenactivated protein kinase and is a significant parameter in breast cancer progression. Clin. Cancer Res. 4, 567–576.PubMedGoogle Scholar
  68. Washio, A., Kitamura, C., Jimi, E., Terashita, M., and Nishihara, T. (2009). Mechanisms involved in suppression of NGF-induced neuronal differentiation of PC12 cells by hyaluronic acid. Exp. Cell Res. 315, 3036–3043.PubMedCrossRefGoogle Scholar
  69. West, D.C., Hampson, I.N., Arnold, F., and Kumar, S. (1985). Angiogenesis induced by degradation products of hyaluronic acid. Science 228, 1324–1326.PubMedCrossRefGoogle Scholar
  70. West, D.C., and Kumar, S. (1989). The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity. Exp. Cell Res. 183, 179–196.PubMedCrossRefGoogle Scholar
  71. Wu, Y., Ip, J.E., Huang, J., Zhang, L., Matsushita, K., Liew, C.C., Pratt, R.E., and Dzau, V.J. (2006). Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circ. Res. 99, 315–322.PubMedCrossRefGoogle Scholar
  72. Xue, Y., Bi, F., Zhang, X., Zhang, S., Pan, Y., Liu, N., Shi, Y., Yao, X., Zheng, Y., and Fan, D. (2006). Role of Rac1 and Cdc42 in hypoxia induced p53 and von Hippel-Lindau suppression and HIF1alpha activation. Int. J. Cancer. 118, 2965–2972.PubMedCrossRefGoogle Scholar
  73. Yang, S.R., Chida, A.S., Bauter, M.R., Shafiq, N., Seweryniak, K., Maggirwar, S.B., Kilty, I., and Rahman, I. (2006). Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am. J. Physiol. Lung Cell Mol. Physiol. 291, 46–57.CrossRefGoogle Scholar
  74. Zampetaki, A., Zeng, L., Margariti, A., Xiao, Q., Li, H., Zhang, Z., Pepe, A.E., Wang, G., Habi, O., deFalco, E., et al. (2010). Histone deacetylase 3 Is critical in endothelial survival and Atherosclerosis development in response to disturbed flow. Circulation 121, 132–142.PubMedCrossRefGoogle Scholar
  75. Zhang, S., Chang, M.C., Zylka, D., Turley, S., Harrison, R., and Turley, E.A. (1998). The hyaluronan receptor RHAMM regulates extracellular-regulated kinase. J. Biol. Chem. 273, 11342–11348.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2012

Authors and Affiliations

  • Deokbum Park
    • 1
  • Youngmi Kim
    • 1
  • Hyunah Kim
    • 1
  • Kyungjong Kim
    • 1
  • Yun-Sil Lee
    • 2
  • Jongseon Choe
    • 3
  • Jang-Hee Hahn
    • 3
  • Hansoo Lee
    • 1
  • Jongwook Jeon
    • 4
  • Chulhee Choi
    • 4
  • Young-Myeong Kim
    • 3
  • Dooil Jeoung
    • 1
    Email author
  1. 1.School of Biological Sciences, College of Natural SciencesKangwon National UniversityChuncheonKorea
  2. 2.College of PharmacyEwha Womans UniversitySeoulKorea
  3. 3.School of MedicineKangwon National UniversityChunchonKorea
  4. 4.Cell Signaling and BioImaging Laboratory, Department of Bio and Brain EngineeringKorea Advanced Institute of Science and TechnologyDaejeonKorea

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