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ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques

  • Author Footnotes
    1 These authors contributed equally to the work.
    Dick Wågsäter
    Correspondence
    Corresponding author at: King Gustaf V Research Institute, Building M1, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden. Tel.: +46 8 51770321; fax: +46 8 311298.
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to the work.
    Hanna Björk
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
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  • Chaoyong Zhu
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
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  • Johan Björkegren
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
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  • Guro Valen
    Affiliations
    Department of Basic Medical Science, Department of Physiology, University of Oslo, Oslo, Norway
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  • Anders Hamsten
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
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  • Per Eriksson
    Affiliations
    Atherosclerosis Research Unit, King Gustav V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden
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  • Author Footnotes
    1 These authors contributed equally to the work.

      Abstract

      Objectives

      Remodeling of extracellular matrix (ECM) plays an important role in inflammatory disorders such as atherosclerosis. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently described family of proteinases that is able to degrade the ECM proteins aggrecan and versican expressed in blood vessels. The purpose of the present study was to analyze the expression and regulation of several ADAMTSs before and after macrophage differentiation and after stimulation with IFN-γ, IL-1β and TNF-α. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.

      Methods and results

      Real time RTPCR showed that, of the nine different ADAMTS members examined, only ADAMTS-4 and -8 were induced during monocyte to macrophage differentiation, which was also seen at protein level. Macrophage expression of ADAMTS-4, -7, -8 and -9 mRNA were enhanced upon stimulation with IFN-γ or TNF-α. Furthermore, immunohistochemical analyses revealed that ADAMTS-4 and -8 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. In addition, ADAMTS-4 expression was upregulated during the development of atherosclerosis in LDLR−/−ApoB100/100 mice. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas, it was significantly higher in aortas from 30–40-week old atherosclerotic animals.

      Conclusion

      The present study suggests that ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. This is the first study associating ADAMTS-4 and -8 expression with atherosclerosis. However, further experiments are required to understand the physiological and pathological functions of ADAMTS in the vascular wall, and tools to measure ADAMTS activity need to be developed.

      Keywords

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      References

        • Wittekind C.
        • Neid M.
        Cancer invasion and metastasis.
        Oncology. 2005; 69: 14-16
        • Burrage P.S.
        • Mix K.S.
        • Brinckerhoff C.E.
        Matrix metalloproteinases: role in arthritis.
        Front Biosci. 2006; 11: 529-543
        • Newby A.C.
        Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture.
        Physiol Rev. 2005; 85: 1-31
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Libby P.
        • Ridker P.M.
        • Maseri A.
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Brauer P.R.
        MMPs—role in cardiovascular development and disease.
        Front Biosci. 2006; 11: 447-478
        • Whatling C.
        • Bjork H.
        • Gredmark S.
        • Hamsten A.
        • Eriksson P.
        Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes.
        J Lipid Res. 2004; 45: 1768-1776
        • Porter S.
        • Clark I.M.
        • Kevorkian L.
        • Edwards D.R.
        The ADAMTS metalloproteinases.
        Biochem J. 2005; 386: 15-27
        • Seals D.F.
        • Courtneidge S.A.
        The ADAMs family of metalloproteases: multidomain proteins with multiple functions.
        Genes Dev. 2003; 17: 7-30
        • Tang B.L.
        ADAMTS: a novel family of extracellular matrix proteases.
        Int J Biochem Cell Biol. 2001; 33: 33-44
        • Kuno K.
        • Matsushima K.
        ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region.
        J Biol Chem. 1998; 273: 13912-13917
        • Kashiwagi M.
        • Tortorella M.
        • Nagase H.
        • Brew K.
        TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5).
        J Biol Chem. 2001; 276: 12501-12504
        • Gao G.
        • Westling J.
        • Thompson V.P.
        • et al.
        Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation.
        J Biol Chem. 2002; 277: 11034-11041
        • Kramerova I.A.
        • Kawaguchi N.
        • Fessler L.I.
        • et al.
        Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases.
        Development. 2000; 127: 5475-5485
        • Kuno K.
        • Kanada N.
        • Nakashima E.
        • et al.
        Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene.
        J Biol Chem. 1997; 272: 556-562
        • Vazquez F.
        • Hastings G.
        • Ortega M.A.
        • et al.
        METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity.
        J Biol Chem. 1999; 274: 23349-23357
        • Evanko S.P.
        • Angello J.C.
        • Wight T.N.
        Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1004-1013
        • Lemire J.M.
        • Braun K.R.
        • Maurel P.
        • et al.
        Versican/PG-M isoforms in vascular smooth muscle cells.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1630-1639
        • Bongrazio M.
        • Baumann C.
        • Zakrzewicz A.
        • Pries A.R.
        • Gaehtgens P.
        Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress.
        Cardiovasc Res. 2000; 47: 384-393
        • Jonsson-Rylander A.C.
        • Nilsson T.
        • Fritsche-Danielson R.
        • et al.
        Role of ADAMTS-1 in atherosclerosis: remodeling of carotid artery, immunohistochemistry, and proteolysis of versican.
        Arterioscler Thromb Vasc Biol. 2005; 25: 180-185
        • Jones G.C.
        • Riley G.P.
        ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis.
        Arthritis Res Ther. 2005; 7: 160-169
        • Sandy J.D.
        • Westling J.
        • Kenagy R.D.
        • et al.
        Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4.
        J Biol Chem. 2001; 276: 13372-13378
        • Tortorella M.D.
        • Arner E.C.
        • Hills R.
        • et al.
        Alpha2-macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes.
        J Biol Chem. 2004; 279: 17554-17561
        • Ishibashi S.
        • Brown M.S.
        • Goldstein J.L.
        • et al.
        Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.
        J Clin Invest. 1993; 92: 883-893
        • Farese R.V.J.
        • Veniant M.M.
        • Cham C.M.
        • et al.
        Phenotypic analysis of mice expressing exclusively apolipoprotein B48 or apolipoprotein B100.
        Proc Natl Acad Sci USA. 1996; 93: 6393-6398
        • Chen F.
        • Eriksson P.
        • Hansson G.K.
        • et al.
        Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque.
        Int J Mol Med. 2005; 15: 57-65
        • Holm S.
        A simple sequentially rejective multiple test procedure.
        Scand J Stat. 1979; 6: 65-70
        • Worley J.R.
        • Baugh M.D.
        • Hughes D.A.
        • et al.
        Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid.
        J Biol Chem. 2003; 278: 51340-51346
        • Tsuzaki M.
        • Guyton G.
        • Garrett W.
        • et al.
        IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells.
        J Orthop Res. 2003; 21: 256-264
        • Demircan K.
        • Hirohata S.
        • Nishida K.
        • et al.
        ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes.
        Arthritis Rheum. 2005; 52: 1451-1460
        • Thirunavukkarasu K.
        • Pei Y.
        • Moore T.L.
        • et al.
        Regulation of the human ADAMTS-4 promoter by transcription factors and cytokines.
        Biochem Biophys Res Commun. 2006; 345: 197-204
        • Beals C.R.
        • Clipstone N.A.
        • Ho S.N.
        • Crabtree G.R.
        Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction.
        Genes Dev. 1997; 11: 824-834
        • Sica A.
        • Dorman L.
        • Viggiano V.
        • et al.
        Interaction of NF-kappaB and NFAT with the interferon-gamma promoter.
        J Biol Chem. 1997; 272: 30412-30420
        • Tsai E.Y.
        • Jain J.
        • Pesavento P.A.
        • Rao A.
        • Goldfeld A.E.
        Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp.
        Mol Cell Biol. 1996; 16: 459-467
        • Yao L.Y.
        • Moody C.
        • Schonherr E.
        • Wight T.N.
        • Sandell L.J.
        Identification of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry.
        Matrix Biol. 1994; 14: 213-225
        • Theocharis A.D.
        • Tsolakis I.
        • Hjerpe A.
        • Karamanos N.K.
        Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0).
        Atherosclerosis. 2001; 154: 367-376
        • Merrilees M.J.
        • Beaumont B.
        • Scott L.J.
        Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency.
        Coron Artery Dis. 2001; 12: 7-16
        • Kenagy R.D.
        • Plaas A.H.
        • Wight T.N.
        Versican degradation and vascular disease.
        Trends Cardiovasc Med. 2006; 16: 209-215
        • Bode-Lesniewska B.
        • Dours-Zimmermann M.T.
        • Odermatt B.F.
        • et al.
        Distribution of the large aggregating proteoglycan versican in adult human tissues.
        J Histochem Cytochem. 1996; 44: 303-312
        • O’Brien K.D.
        • Olin K.L.
        • Alpers C.E.
        • et al.
        Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: colocalization of biglycan with apolipoproteins.
        Circulation. 1998; 98: 519-527
        • Matsuura R.
        • Isaka N.
        • Imanaka-Yoshida K.
        • et al.
        Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty.
        J Pathol. 1996; 180: 311-316
        • Strom A.
        • Ahlqvist E.
        • Franzen A.
        • Heinegard D.
        • Hultgardh-Nilsson A.
        Extracellular matrix components in atherosclerotic arteries of Apo E/LDL receptor deficient mice: an immunohistochemical study.
        Histol Histopathol. 2004; 19: 337-347