Advertisement

Homeobox gene HOXA9 inhibits nuclear factor-kappa B dependent activation of endothelium

  • Author Footnotes
    1 Present address: Cardiovascular Institute, University of Pennsylvania School of Medicine, 943 BRB II, 421 Curie Boulevard, Philadelphia, PA 19104, United States. Tel.: +1 215 746 6324; fax: +1 215 573 2094.
    Chinmay M. Trivedi
    Footnotes
    1 Present address: Cardiovascular Institute, University of Pennsylvania School of Medicine, 943 BRB II, 421 Curie Boulevard, Philadelphia, PA 19104, United States. Tel.: +1 215 746 6324; fax: +1 215 573 2094.
    Affiliations
    Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC-29209, United States

    Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, United States
    Search for articles by this author
  • Rekha C. Patel
    Affiliations
    Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, United States
    Search for articles by this author
  • Chandrashekhar V. Patel
    Correspondence
    Corresponding author at: Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Building 4, Room C16, 6439 Garners Ferry Road, Columbia, SC 29209, United States. Tel.: +1 803 733 3274; fax: +1 803 733 1533.
    Affiliations
    Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC-29209, United States
    Search for articles by this author
  • Author Footnotes
    1 Present address: Cardiovascular Institute, University of Pennsylvania School of Medicine, 943 BRB II, 421 Curie Boulevard, Philadelphia, PA 19104, United States. Tel.: +1 215 746 6324; fax: +1 215 573 2094.

      Abstract

      Cytokine-induced expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin, on activated endothelial cells (EC) plays an essential role in the development of inflammatory diseases like atherosclerosis. Transcription factor nuclear factor-kappa B (NF-κB) is mainly responsible for the induced expression of these adhesion molecules in response to pro-inflammatory cytokines. The mechanisms that maintain EC in a “basal” state and negatively regulate EC activation remain to be characterized. HOXA9 is a homeobox transcription factor expressed in EC and its expression is rapidly down-regulated in response to inflammatory signals. In the present study, we demonstrate that HOXA9 overexpression inhibits the induction of ICAM-1, VCAM-1, and E-selectin in response to pro-inflammatory cytokines. HOXA9 inhibits the adhesion molecule expression by inhibiting NF-κB dependent transcriptional activation of these promoters. HOXA9 inhibits EC activation downstream of NF-κB nuclear localization by interfering with NF-κB DNA binding, but not transactivation capacity. Trichostatin A (TSA) rescues HOXA9 mediated suppression of NF-κB activity, but HOXA9 interaction with p300 is not responsible for inhibition of EC activation. Thus, our results suggest involvement of HOXA9 in maintaining the “basal” state of EC and demonstrate that downregulation of HOXA9 is an essential event during EC activation in response to inflammatory signals.

      Abbreviations:

      EC (endothelial cells), ICAM-1 (intracellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), HUVECs (human umbilical vein endothelial cells), HOX (homeobox), TNF-α (tumor necrosis factor-α), LPS (lipopolysaccharide), PMA (phorbol myristate acetate), IL-1β (interleukin-1β), NF-κB (nuclear factor-κB)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Collins T.
        • Cybulsky M.I.
        NF-kappaB: pivotal mediator or innocent bystander in atherogenesis?.
        J Clin Invest. 2001; 107: 255-264
        • Schindler U.
        • Baichwal V.R.
        Three NF-kappa B binding sites in the human E-selectin gene required for maximal tumor necrosis factor alpha-induced expression.
        Mol Cell Biol. 1994; 14: 5820-5831
        • Iademarco M.F.
        • Barks J.L.
        • Dean D.C.
        Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells.
        J Clin Invest. 1995; 95: 264-271
        • Brostjan C.
        • Anrather J.
        • Csizmadia V.
        • et al.
        Glucocorticoids inhibit E-selectin expression by targeting NF-kappaB and not ATF/c-Jun.
        J Immunol. 1997; 158: 3836-3844
        • Krumlauf R.
        Hox genes in vertebrate development.
        Cell. 1994; 78: 191-201
        • Levine M.
        • Rubin G.M.
        • Tjian R.
        Human DNA sequences homologous to a protein coding region conserved between homeotic genes of Drosophila.
        Cell. 1984; 38: 667-673
        • Shen W.F.
        • Rozenfeld S.
        • Kwong A.
        • et al.
        HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells.
        Mol Cell Biol. 1999; 19: 3051-3061
        • Shen W.-F.
        • Krishnan K.
        • Lawrence H.J.
        • et al.
        The HOX homeodomain proteins block CBP histone acetyltransferase activity.
        Mol Cell Biol. 2001; 21: 7509-7522
        • Shi X.
        • Bai S.
        • Li L.
        • et al.
        Hoxa-9 represses transforming growth factor-beta-induced osteopontin gene transcription.
        J Biol Chem. 2001; 276: 850-855
        • Gorski D.H.
        • Walsh K.
        The role of homeobox genes in vascular remodeling and angiogenesis.
        Circ Res. 2000; 87: 865-872
        • Myers C.
        • Charboneau A.
        • Cheung I.
        • et al.
        Sustained expression of homeobox D10 inhibits angiogenesis.
        Am J Pathol. 2002; 161: 2099-2109
        • Boudreau N.J.
        • Varner J.A.
        The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis.
        J Biol Chem. 2004; 279: 4862-4868
        • Patel C.V.
        • Sharangpani R.
        • Bandyopadhyay S.
        • et al.
        Endothelial cells express a novel, tumor necrosis factor-alpha-regulated variant of HOXA9.
        J Biol Chem. 1999; 274: 1415-1422
        • Degitz K.
        • Li L.J.
        • Caughman S.W.
        Cloning and characterization of the 5′-transcriptional regulatory region of the human intercellular adhesion molecule 1 gene.
        J Biol Chem. 1991; 266: 14024-14030
        • Neish A.S.
        • Read M.A.
        • Thanos D.
        • et al.
        Endothelial interferon regulatory factor 1 cooperates with NF-kappa B as a transcriptional activator of vascular cell adhesion molecule 1.
        Mol Cell Biol. 1995; 15: 2558-2569
        • Chen L.-F.
        • Fischle W.
        • Verdin E.
        • et al.
        Duration of nuclear NF-kappa B action regulated by reversible acetylation.
        Science. 2001; 293: 1653-1657
        • Shu H.B.
        • Agranoff A.B.
        • Nabel E.G.
        • et al.
        Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells.
        Mol Cell Biol. 1993; 13: 6283-6289
        • Lewis H.
        • Kaszubska W.
        • DeLamarter J.F.
        • et al.
        Cooperativity between two NF-kappa B complexes, mediated by high-mobility-group protein I(Y), is essential for cytokine-induced expression of the E-selectin promoter.
        Mol Cell Biol. 1994; 14: 5701-5709
        • Rahman A.
        • True A.L.
        • Anwar K.N.
        • et al.
        Galpha(q) and Gbetagamma regulate PAR-1 signaling of thrombin-induced NF-kappaB activation and ICAM-1 transcription in endothelial cells.
        Circ Res. 2002; 91: 398-405
        • Collins T.
        • Read M.A.
        • Neish A.S.
        • et al.
        Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers.
        FASEB J. 1995; 9: 899-909
        • Meyer C.F.
        • Wang X.
        • Chang C.
        • et al.
        Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation.
        J Biol Chem. 1996; 271: 8971-8976
        • Chen L.-F.
        • Greene W.C.
        Shaping the nuclear action of NF-[kappa]B.
        Nat Rev Mol Cell Biol. 2004; 5: 392-401
        • Chien C.T.
        • Bartel P.L.
        • Sternglanz R.
        • et al.
        The two-hybrid system: a method to identify and clone genes for proteins that interact with a protein of interest.
        Proc Natl Acad Sci USA. 1991; 88: 9578-9582
        • Perkins N.D.
        • Felzien L.K.
        • Betts J.C.
        • et al.
        Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator.
        Science. 1997; 275: 523-527
        • Lu Y.
        • Goldenberg I.
        • Bei L.
        • et al.
        HoxA10 represses gene transcription in undifferentiated myeloid cells by interaction with histone deacetylase 2.
        J Biol Chem. 2003; 278: 47792-47802
        • Calvo K.R.
        • Sykes D.B.
        • Pasillas M.
        • et al.
        Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression.
        Mol Cell Biol. 2000; 20: 3274-3285
        • Bruhl T.
        • Urbich C.
        • Aicher D.
        • et al.
        Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation.
        Circ Res. 2004; 94: 743-751