Glycosaminoglycans in Atherosclerosis and Thrombosis

  • C. P. VicenteEmail author
  • J. A. P. Godoy
  • C. C. Werneck
Part of the Biology of Extracellular Matrix book series (BEM)


The endothelium plays a crucial role in regulating vascular tone, inflammatory responses, thrombosis, and atherosclerosis. Part of these activities is regulated by the presence of glycosaminoglycans (GAGs) in the vessel wall and in the extracellular matrix (ECM) surrounding it. GAGs in atherosclerosis can help regulate atherogenesis through their ability to retain lipoproteins in the vessel wall. Prolonged retention of lipoproteins may render them susceptible to chemical modifications, leading to their aggregation, cellular uptake, and lipid accumulation. GAGs can also act as anticoagulants by interacting with proteins like antitrombin and heparin cofator II and thereby promoting their activation and increasing their ability to inhibit thrombin. In this chapter, we discuss the roles of different GAGs located in the vessel wall and ECM, focusing on understanding the mechanisms of action of these molecules in atherosclerosis and thrombosis.


Heparan Sulfate Chondroitin Sulfate Dermatan Sulfate Heparan Sulfate Chain Hemodynamic Shear Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo – FAPESP 2007/01112-6, 2010/11474-5 (CPV) and 2009/00950-3, 2006/06560-4 (CCW), 2010/01119-3 (JAPG) and Conselho Nacional de Desenvolvimento Científico e Tecnológico- CNPq – 470608/2009-9 (CCW)


  1. Aruffo A, Stamenkovic I et al (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61(7):1303–1313PubMedGoogle Scholar
  2. Ballinger ML, Nigro J et al (2004) Regulation of glycosaminoglycan structure and atherogenesis. Cell Mol Life Sci 61(11):1296–1306PubMedGoogle Scholar
  3. Ballinger ML, Ivey ME et al (2009) Endothelin-1 activates ETA receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL. Atherosclerosis 205(2):451–457PubMedGoogle Scholar
  4. Bernfield M, Gotte M et al (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777PubMedGoogle Scholar
  5. Bobik A, Grooms A et al (1990) Growth factor activity of endothelin on vascular smooth muscle. Am J Physiol 258(3 Pt 1):C408–C415PubMedGoogle Scholar
  6. Bowe MA, Mendis DB et al (2000) The small leucine-rich repeat proteoglycan biglycan binds to alpha-dystroglycan and is upregulated in dystrophic muscle. J Cell Biol 148(4):801–810PubMedGoogle Scholar
  7. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820PubMedGoogle Scholar
  8. Buchanan MR, Maclean GA et al (2001) Selective and sustained inhibition of surface-bound thrombin activity by intimatan/heparin cofactor II and its relevance to assessing systemic anticoagulation in vivo, ex vivo and in vitro. Thromb Haemost 86(3):909–913PubMedGoogle Scholar
  9. Camejo G, Olsson U et al (2002) The extracellular matrix on atherogenesis and diabetes-associated vascular disease. Atheroscler Suppl 3(1):3–9PubMedGoogle Scholar
  10. Cardoso LE, Mourao PA (1994) Glycosaminoglycan fractions from human arteries presenting diverse susceptibilities to atherosclerosis have different binding affinities to plasma LDL. Arterioscler Thromb 14(1):115–124PubMedGoogle Scholar
  11. Casu B, Guerrini M et al (2004) Structural and conformational aspects of the anticoagulant and anti-thrombotic activity of heparin and dermatan sulfate. Curr Pharm Des 10(9):939–949PubMedGoogle Scholar
  12. Cavalcante MC, Allodi S et al (2000) Occurrence of heparin in the invertebrate styela plicata (Tunicata) is restricted to cell layers facing the outside environment. An ancient role in defense? J Biol Chem 275(46):36189–36186PubMedGoogle Scholar
  13. Ceroni A, Dell A et al (2007) The GlycanBuilder: a fast, intuitive and flexible software tool for building and displaying glycan structures. Source Code Biol Med 2:3PubMedGoogle Scholar
  14. Chai S, Chai Q et al (2005) Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis. Circ Res 96(5):583–591PubMedGoogle Scholar
  15. Chang MY, Potter-Perigo S et al (2000) Oxidized low density lipoproteins regulate synthesis of monkey aortic smooth muscle cell proteoglycans that have enhanced native low density lipoprotein binding properties. J Biol Chem 275(7):4766–4773PubMedGoogle Scholar
  16. Chatzizisis YS, Coskun AU et al (2007) Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 49(25):2379–2393PubMedGoogle Scholar
  17. Clark RA (2001) Fibrin and wound healing. Ann N Y Acad Sci 936:355–367PubMedGoogle Scholar
  18. Corsi A, Xu T et al (2002) Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues. J Bone Miner Res 17(7):1180–1189PubMedGoogle Scholar
  19. Cuff CA, Kothapalli D et al (2001) The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation. J Clin Invest 108(7):1031–1040PubMedGoogle Scholar
  20. Cunningham KS, Gotlieb AI (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 85(1):9–23PubMedGoogle Scholar
  21. Danielson KG, Baribault H et al (1997) Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol 136(3):729–743PubMedGoogle Scholar
  22. Davignon J (2004) The cardioprotective effects of statins. Curr Atheroscler Rep 6(1):27–35PubMedGoogle Scholar
  23. de Mattos DA, Stelling MP et al (2008) Heparan sulfates from arteries and veins differ in their antithrombin-mediated anticoagulant activity. J Thromb Haemost 6(11):1987–1990PubMedGoogle Scholar
  24. Denis CV, Wagner DD (2007) Platelet adhesion receptors and their ligands in mouse models of thrombosis. Arterioscler Thromb Vasc Biol 27(4):728–739PubMedGoogle Scholar
  25. Dietrich CP, Tersariol IL et al (1998) Structure of heparan sulfate: identification of variable and constant oligosaccharide domains in eight heparan sulfates of different origins. Cell Mol Biol (Noisy-le-grand) 44(3):417–429Google Scholar
  26. Duan W, Paka L et al (2005) Distinct effects of glucose and glucosamine on vascular endothelial and smooth muscle cells: evidence for a protective role for glucosamine in atherosclerosis. Cardiovasc Diabetol 4:16PubMedGoogle Scholar
  27. Dugan TA, Yang VW et al (2006) Decorin modulates fibrin assembly and structure. J Biol Chem 281(50):38208–38216PubMedGoogle Scholar
  28. Edwards IJ, Xu H et al (1994) Interleukin-1 upregulates decorin production by arterial smooth muscle cells. Arterioscler Thromb 14(7):1032–1039PubMedGoogle Scholar
  29. Edwards IJ, Wagner JD et al (2004) Arterial heparan sulfate is negatively associated with hyperglycemia and atherosclerosis in diabetic monkeys. Cardiovasc Diabetol 3:6PubMedGoogle Scholar
  30. Eikelboom JW, Anand SS et al (2000) Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 355(9219):1936–1942PubMedGoogle Scholar
  31. Endemann DH, Schiffrin EL (2004) Endothelial dysfunction. J Am Soc Nephrol 15(8):1983–1992PubMedGoogle Scholar
  32. Endler G, Klimesch A et al (2002) Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 117(2):399–404PubMedGoogle Scholar
  33. Esko JD, Lindahl U (2001) Molecular diversity of heparan sulfate. J Clin Invest 108(2):169–173PubMedGoogle Scholar
  34. Esko JD, Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71:435–471PubMedGoogle Scholar
  35. Evanko SP, Raines EW et al (1998) Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am J Pathol 152(2):533–546PubMedGoogle Scholar
  36. Evanko SP, Angello JC et al (1999) Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19(4):1004–1013PubMedGoogle Scholar
  37. Fischer JW, Steitz SA et al (2004) Decorin promotes aortic smooth muscle cell calcification and colocalizes to calcified regions in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 24(12):2391–2396PubMedGoogle Scholar
  38. Forbes JM, Yee LT et al (2004) Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes 53(7):1813–1823PubMedGoogle Scholar
  39. Fraser JR, Laurent TC et al (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242(1):27–33PubMedGoogle Scholar
  40. Furie B, Furie BC (2008) Mechanisms of thrombus formation. N Engl J Med 359(9):938–949PubMedGoogle Scholar
  41. Gettins PG (2002) Serpin structure, mechanism, and function. Chem Rev 102(12):4751–4804PubMedGoogle Scholar
  42. Gordillo GM, Sen CK (2003) Revisiting the essential role of oxygen in wound healing. Am J Surg 186(3):259–263PubMedGoogle Scholar
  43. Gotlieb AI (2005) Atherosclerosis and acute coronary syndromes. Cardiovasc Pathol 14(4):181–184PubMedGoogle Scholar
  44. Gozzo AJ, Nunes VA et al (2002) Glycosaminoglycans affect the action of human plasma kallikrein on kininogen hydrolysis and inflammation. Int Immunopharmacol 2(13–14):1861–1865PubMedGoogle Scholar
  45. Greiling D, Clark RA (1997) Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci 110(Pt 7):861–870PubMedGoogle Scholar
  46. Guretzki HJ, Gerbitz KD et al (1994) Atherogenic levels of low density lipoprotein alter the permeability and composition of the endothelial barrier. Atherosclerosis 107(1):15–24PubMedGoogle Scholar
  47. HajMohammadi S, Enjyoji K et al (2003) Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis. J Clin Invest 111(7):989–999PubMedGoogle Scholar
  48. Hallmann R, Horn N et al (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85(3):979–1000PubMedGoogle Scholar
  49. Harenberg J (2009) LMWH – new mechanisms of action. Thromb Res 123(Suppl 3):S1–S4PubMedGoogle Scholar
  50. Hashimura K, Sudhir K et al (2005) Androgens stimulate human vascular smooth muscle cell proteoglycan biosynthesis and increase lipoprotein binding. Endocrinology 146(4):2085–2090PubMedGoogle Scholar
  51. He L, Vicente CP et al (2002) Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Invest 109(2):213–219PubMedGoogle Scholar
  52. He L, Giri TK et al (2008) Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II. Blood 111(8):4118–4125PubMedGoogle Scholar
  53. Hennan JK, Hong TT et al (2002) Intimatan prevents arterial and venous thrombosis in a canine model of deep vessel wall injury. J Pharmacol Exp Ther 301(3):1151–1156PubMedGoogle Scholar
  54. Hirsh J (1998) Low-molecular-weight heparin for the treatment of venous thromboembolism. Am Heart J 135(6 Pt 3 Su):S336–S342PubMedGoogle Scholar
  55. Hogg PJ, Jackson CM (1989) Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 86(10):3619–3623PubMedGoogle Scholar
  56. Hong TT, Van Gorp CL et al (2006) Intimatan (dermatan 4, 6-O-disulfate) prevents rethrombosis after successful thrombolysis in the canine model of deep vessel wall injury. Thromb Res 117(3):333–342PubMedGoogle Scholar
  57. Horsewood P, Warkentin TE et al (1996) The epitope specificity of heparin-induced thrombocytopenia. Br J Haematol 95(1):161–167PubMedGoogle Scholar
  58. Huang F, Thompson JC et al (2008) Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development. J Lipid Res 49(3):521–530PubMedGoogle Scholar
  59. Hultgardh-Nilsson A, Durbeej M (2007) Role of the extracellular matrix and its receptors in smooth muscle cell function: implications in vascular development and disease. Curr Opin Lipidol 18(5):540–545PubMedGoogle Scholar
  60. Hurt-Camejo E, Olsson U et al (1997) Cellular consequences of the association of apoB lipoproteins with proteoglycans. Potential contribution to atherogenesis. Arterioscler Thromb Vasc Biol 17(6):1011–1017PubMedGoogle Scholar
  61. Ignarro LJ, Buga GM et al (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84(24):9265–9269PubMedGoogle Scholar
  62. Ilangumaran S, Briol A et al (1998) CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes. Blood 91(10):3901–3908PubMedGoogle Scholar
  63. Iozzo RV, Cohen IR et al (1994) The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 302(Pt 3):625–639PubMedGoogle Scholar
  64. Isaka Y, Brees DK et al (1996) Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 2(4):418–423PubMedGoogle Scholar
  65. Itano N, Sawai T et al (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274(35):25085–25092PubMedGoogle Scholar
  66. Ivey ME, Little PJ (2008) Thrombin regulates vascular smooth muscle cell proteoglycan synthesis via PAR-1 and multiple downstream signalling pathways. Thromb Res 123(2):288–297PubMedGoogle Scholar
  67. Jarvelainen HT, Kinsella MG et al (1991) Differential expression of small chondroitin/dermatan sulfate proteoglycans, PG-I/biglycan and PG-II/decorin, by vascular smooth muscle and endothelial cells in culture. J Biol Chem 266(34):23274–23281PubMedGoogle Scholar
  68. Jennings LK (2009) Role of platelets in atherothrombosis. Am J Cardiol 103(3 Suppl):4A–10APubMedGoogle Scholar
  69. Jeziorska M, McCollum C et al (1998) Calcification in atherosclerotic plaque of human carotid arteries: associations with mast cells and macrophages. J Pathol 185(1):10–17PubMedGoogle Scholar
  70. Kaji T, Sakurai S et al (2004) Characterization of chondroitin/dermatan sulfate proteoglycans synthesized by bovine retinal pericytes in culture. Biol Pharm Bull 27(11):1763–1768PubMedGoogle Scholar
  71. Kallunki P, Tryggvason K (1992) Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Cell Biol 116(2):559–571PubMedGoogle Scholar
  72. Kelton JG (2002) Heparin-induced thrombocytopenia: an overview. Blood Rev 16(1):77–80PubMedGoogle Scholar
  73. Kelton JG (2005) The pathophysiology of heparin-induced thrombocytopenia: biological basis for treatment. Chest 127(2 Suppl):9S–20SPubMedGoogle Scholar
  74. Knudson W, Chow G et al (2002) CD44-mediated uptake and degradation of hyaluronan. Matrix Biol 21(1):15–23PubMedGoogle Scholar
  75. Kolb M, Margetts PJ et al (2001) Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol 280(6):L1327–L1334PubMedGoogle Scholar
  76. Kovanen PT, Pentikainen MO (1999) Decorin links low-density lipoproteins (LDL) to collagen: a novel mechanism for retention of LDL in the atherosclerotic plaque. Trends Cardiovasc Med 9(3–4):86–91PubMedGoogle Scholar
  77. Kreuger J, Matsumoto T et al (2002) Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function. Embo J 21(23):6303–6311PubMedGoogle Scholar
  78. Krumdieck R, Hook M et al (1992) The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex. J Immunol 149(11):3695–3701PubMedGoogle Scholar
  79. Kultti A, Rilla K et al (2006) Hyaluronan synthesis induces microvillus-like cell surface protrusions. J Biol Chem 281(23):15821–15828PubMedGoogle Scholar
  80. Laurent TC, Fraser JR (1992) Hyaluronan. Faseb J 6(7):2397–2404PubMedGoogle Scholar
  81. Levy JH, Hursting MJ (2007) Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am 21(1):65–88PubMedGoogle Scholar
  82. Libby P (2006) Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83(2):456S–460SPubMedGoogle Scholar
  83. Lindahl U, Kusche-Gullberg M et al (1998) Regulated diversity of heparan sulfate. J Biol Chem 273(39):24979–24982PubMedGoogle Scholar
  84. Little PJ, Tannock L et al (2002) Proteoglycans synthesized by arterial smooth muscle cells in the presence of transforming growth factor-beta1 exhibit increased binding to LDLs. Arterioscler Thromb Vasc Biol 22(1):55–60PubMedGoogle Scholar
  85. Little PJ, Ballinger ML et al (2007) Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis. Vasc Health Risk Manag 3(1):117–124PubMedGoogle Scholar
  86. Little PJ, Ballinger ML et al (2008) Biosynthesis of natural and hyperelongated chondroitin sulfate glycosaminoglycans: new insights into an elusive process. Open Biochem J 2:135–142PubMedGoogle Scholar
  87. Liu J, Pedersen LC (2007) Anticoagulant heparan sulfate: structural specificity and biosynthesis. Appl Microbiol Biotechnol 74(2):263–272PubMedGoogle Scholar
  88. Liu J, Thorp SC (2002) Cell surface heparan sulfate and its roles in assisting viral infections. Med Res Rev 22(1):1–25PubMedGoogle Scholar
  89. Maimone MM, Tollefsen DM (1988) Activation of heparin cofactor II by heparin oligosaccharides. Biochem Biophys Res Commun 152(3):1056–1061PubMedGoogle Scholar
  90. Malavaki C, Mizumoto S et al (2008) Recent advances in the structural study of functional chondroitin sulfate and dermatan sulfate in health and disease. Connect Tissue Res 49(3):133–139PubMedGoogle Scholar
  91. Marcus AJ, Broekman MJ et al (2002) COX inhibitors and thromboregulation. N Engl J Med 347(13):1025–1026PubMedGoogle Scholar
  92. Matsuda M, Shimomura I et al (2002) Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277(40):37487–37491PubMedGoogle Scholar
  93. Medeiros GF, Mendes A et al (2000) Distribution of sulfated glycosaminoglycans in the animal kingdom: widespread occurrence of heparin-like compounds in invertebrates. Biochim Biophys Acta 1475(3):287–294PubMedGoogle Scholar
  94. Merrilees MJ, Beaumont B et al (2001) Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency. Coron Artery Dis 12(1):7–16PubMedGoogle Scholar
  95. Monzavi-Karbassi B, Stanley JS et al (2007) Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines. Int J Cancer 120(6):1179–1191PubMedGoogle Scholar
  96. Mourao PA, Pereira MS et al (1996) Structure and anticoagulant activity of a fucosylated chondroitin sulfate from echinoderm. Sulfated fucose branches on the polysaccharide account for its high anticoagulant action. J Biol Chem 271(39):23973–23984PubMedGoogle Scholar
  97. Murata K, Yokoyama Y (1982) Acidic glycosaminoglycan, lipid and water contents in human coronary arterial branches. Atherosclerosis 45(1):53–65PubMedGoogle Scholar
  98. Myles T, Church FC et al (1998) Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J Biol Chem 273(47):31203–31208PubMedGoogle Scholar
  99. Nader HB, Dietrich CP et al (1987) Heparin sequences in the heparan sulfate chains of an endothelial cell proteoglycan. Proc Natl Acad Sci U S A 84(11):3565–3569PubMedGoogle Scholar
  100. Nader HB, Lopes CC et al (2004) Heparins and heparinoids: occurrence, structure and mechanism of antithrombotic and hemorrhagic activities. Curr Pharm Des 10(9):951–966PubMedGoogle Scholar
  101. Nili N, Cheema AN et al (2003) Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty. Am J Pathol 163(3):869–878PubMedGoogle Scholar
  102. Noonan DM, Fulle A et al (1991) The complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin A chain, low density lipoprotein-receptor, and the neural cell adhesion molecule. J Biol Chem 266(34):22939–22947PubMedGoogle Scholar
  103. Okamoto Y, Kihara S et al (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106(22):2767–2770PubMedGoogle Scholar
  104. Pacheco RG, Vicente CP et al (2000) Different antithrombotic mechanisms among glycosaminoglycans revealed with a new fucosylated chondroitin sulfate from an echinoderm. Blood Coagul Fibrinolysis 11(6):563–573PubMedGoogle Scholar
  105. Palmer RM, Ferrige AG et al (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526PubMedGoogle Scholar
  106. Pavao MS, Mourao PA et al (1995) A unique dermatan sulfate-like glycosaminoglycan from ascidian. Its structure and the effect of its unusual sulfation pattern on anticoagulant activity. J Biol Chem 270(52):31027–31036PubMedGoogle Scholar
  107. Pavao MS, Aiello KR et al (1998) Highly sulfated dermatan sulfates from Ascidians. Structure versus anticoagulant activity of these glycosaminoglycans. J Biol Chem 273(43):27848–27857PubMedGoogle Scholar
  108. Philipson LH, Schwartz NB (1984) Subcellular localization of hyaluronate synthetase in oligodendroglioma cells. J Biol Chem 259(8):5017–5023PubMedGoogle Scholar
  109. Pignone M, Phillips C et al (2000) Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 321(7267):983–986PubMedGoogle Scholar
  110. Pillarisetti S, Paka L et al (1997) Endothelial cell heparanase modulation of lipoprotein lipase activity. Evidence that heparan sulfate oligosaccharide is an extracellular chaperone. J Biol Chem 272(25):15753–15759PubMedGoogle Scholar
  111. Prehm P (1984) Hyaluronate is synthesized at plasma membranes. Biochem J 220(2):597–600PubMedGoogle Scholar
  112. Rosenberg RD, Shworak NW et al (1997) Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 100(11 Suppl):S67–S75PubMedGoogle Scholar
  113. Ross R (1999) Atherosclerosis is an inflammatory disease. Am Heart J 138(5 Pt 2):S419–S420PubMedGoogle Scholar
  114. Rote WE, Werns SW et al (1993) Platelet GPIIb/IIIa receptor inhibition by SC-49992 prevents thrombosis and rethrombosis in the canine carotid artery. Cardiovasc Res 27(3):500–507PubMedGoogle Scholar
  115. Rydel TJ, Yin M et al (1994) Crystallographic structure of human gamma-thrombin. J Biol Chem 269(35):22000–22006PubMedGoogle Scholar
  116. Sakr SW, Potter-Perigo S et al (2008) Hyaluronan accumulation is elevated in cultures of low density lipoprotein receptor-deficient cells and is altered by manipulation of cell cholesterol content. J Biol Chem 283(52):36195–36204PubMedGoogle Scholar
  117. Schmidt G, Hausser H et al (1991) Interaction of the small proteoglycan decorin with fibronectin. Involvement of the sequence NKISK of the core protein. Biochem J 280(Pt 2):411–414PubMedGoogle Scholar
  118. Schonherr E, Sunderkotter C et al (2004) Decorin deficiency leads to impaired angiogenesis in injured mouse cornea. J Vasc Res 41(6):499–508PubMedGoogle Scholar
  119. Segev A, Nili N et al (2004) The role of perlecan in arterial injury and angiogenesis. Cardiovasc Res 63(4):603–610PubMedGoogle Scholar
  120. Seike M, Ikeda M et al (2006) Hyaluronan forms complexes with low density lipoprotein while also inducing foam cell infiltration in the dermis. J Dermatol Sci 41(3):197–204PubMedGoogle Scholar
  121. Sen CK (2003) The general case for redox control of wound repair. Wound Repair Regen 11(6):431–438PubMedGoogle Scholar
  122. Shirk RA, Parthasarathy N et al (2000) Altered dermatan sulfate structure and reduced heparin cofactor II-stimulating activity of biglycan and decorin from human atherosclerotic plaque. J Biol Chem 275(24):18085–18092PubMedGoogle Scholar
  123. Skalen K, Gustafsson M et al (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417(6890):750–754PubMedGoogle Scholar
  124. Srinivasan SR, Yost K et al (1980) Lipoprotein-hyaluronate associations in human aorta fibrous plaque lesions. Atherosclerosis 36(1):25–37PubMedGoogle Scholar
  125. Stern R (2003) Devising a pathway for hyaluronan catabolism: are we there yet? Glycobiology 13(12):105R–115RPubMedGoogle Scholar
  126. Stevens RL, Colombo M et al (1976) The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest 58(2):470–481PubMedGoogle Scholar
  127. Stocker R, Keaney JF Jr (2004) Role of oxidative modifications in atherosclerosis. Physiol Rev 84(4):1381–1478PubMedGoogle Scholar
  128. Stoll G, Bendszus M (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37(7):1923–1932PubMedGoogle Scholar
  129. Tabata T, Mine S et al (2007) Low molecular weight hyaluronan increases the Uptaking of oxidized LDL into monocytes. Endocr J 54(5):685–693PubMedGoogle Scholar
  130. Taylor KR, Gallo RL (2006) Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. Faseb J 20(1):9–22PubMedGoogle Scholar
  131. Thieszen SL, Rosenquist TH (1995) Expression of collagens and decorin during aortic arch artery development: implications for matrix pattern formation. Matrix Biol 14(7):573–582PubMedGoogle Scholar
  132. Tollefsen DM (2007) Heparin cofactor II modulates the response to vascular injury. Arterioscler Thromb Vasc Biol 27(3):454–460PubMedGoogle Scholar
  133. Tollefsen DM, Pestka CA et al (1983) Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 258(11):6713–6716PubMedGoogle Scholar
  134. Tovar AM, de Mattos DA et al (2005) Dermatan sulfate is the predominant antithrombotic glycosaminoglycan in vessel walls: implications for a possible physiological function of heparin cofactor II. Biochim Biophys Acta 1740(1):45–53PubMedGoogle Scholar
  135. Tran PK, Tran-Lundmark K et al (2004) Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ Res 94(4):550–558PubMedGoogle Scholar
  136. Tran PK, Agardh HE et al (2007) Reduced perlecan expression and accumulation in human carotid atherosclerotic lesions. Atherosclerosis 190(2):264–270PubMedGoogle Scholar
  137. Tran-Lundmark K, Tran PK et al (2008) Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ Res 103(1):43–52PubMedGoogle Scholar
  138. Trowbridge JM, Gallo RL (2002) Dermatan sulfate: new functions from an old glycosaminoglycan. Glycobiology 12(9):117R–125RPubMedGoogle Scholar
  139. Tumova S, Woods A et al (2000) Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. Int J Biochem Cell Biol 32(3):269–288PubMedGoogle Scholar
  140. Vicente CP, He L et al (2004) Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice. Blood 104(13):3965–3970PubMedGoogle Scholar
  141. Volpi N (2006) Therapeutic applications of glycosaminoglycans. Curr Med Chem 13(15):1799–1810PubMedGoogle Scholar
  142. Wahab NA, Parker S et al (2000) The decorin high glucose response element and mechanism of its activation in human mesangial cells. J Am Soc Nephrol 11(9):1607–1619PubMedGoogle Scholar
  143. Wakefield TW, Caprini J et al (2008) Thromboembolic diseases. Curr Probl Surg 45(12):844–899PubMedGoogle Scholar
  144. Weigel PH, Hascall VC et al (1997) Hyaluronan synthases. J Biol Chem 272(22):13997–14000PubMedGoogle Scholar
  145. Weis SM, Zimmerman SD et al (2005) A role for decorin in the remodeling of myocardial infarction. Matrix Biol 24(4):313–324PubMedGoogle Scholar
  146. Weitz JI (2003) Heparan sulfate: antithrombotic or not? J Clin Invest 111(7):952–954PubMedGoogle Scholar
  147. Whinna HC, Choi HU et al (1993) Interaction of heparin cofactor II with biglycan and decorin. J Biol Chem 268(6):3920–3924PubMedGoogle Scholar
  148. Whitelock JM, Iozzo RV (2005) Heparan sulfate: a complex polymer charged with biological activity. Chem Rev 105(7):2745–2764PubMedGoogle Scholar
  149. Wight TN (2002) Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 14(5):617–623PubMedGoogle Scholar
  150. Wight TN (2008) Arterial remodeling in vascular disease: a key role for hyaluronan and versican. Front Biosci 13:4933–4937PubMedGoogle Scholar
  151. Wight TN, Merrilees MJ (2004) Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 94(9):1158–1167PubMedGoogle Scholar
  152. Wilkinson TS, Bressler SL et al (2006) Overexpression of hyaluronan synthases alters vascular smooth muscle cell phenotype and promotes monocyte adhesion. J Cell Physiol 206(2):378–385PubMedGoogle Scholar
  153. Williams KJ, Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15(5):551–561PubMedGoogle Scholar
  154. Wilson PG, Thompson JC et al (2008) Serum amyloid A, but not C-reactive protein, stimulates vascular proteoglycan synthesis in a pro-atherogenic manner. Am J Pathol 173(6):1902–1910PubMedGoogle Scholar
  155. Winnemoller M, Schmidt G et al (1991) Influence of decorin on fibroblast adhesion to fibronectin. Eur J Cell Biol 54(1):10–17PubMedGoogle Scholar
  156. Winnemoller M, Schon P et al (1992) Interactions between thrombospondin and the small proteoglycan decorin: interference with cell attachment. Eur J Cell Biol 59(1):47–55PubMedGoogle Scholar
  157. Witztum JL (1994a) The oxidation hypothesis of atherosclerosis. Lancet 344(8925):793–795PubMedGoogle Scholar
  158. Witztum JL (1994b) The role of oxidized LDL in the atherogenic process. J Atheroscler Thromb 1(2):71–75PubMedGoogle Scholar
  159. Wu ZL, Zhang L et al (2003) The involvement of heparan sulfate (HS) in FGF1/HS/FGFR1 signaling complex. J Biol Chem 278(19):17121–17129PubMedGoogle Scholar
  160. Xu T, Bianco P et al (1998) Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat Genet 20(1):78–82PubMedGoogle Scholar
  161. Yamaguchi Y, Mann DM et al (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346(6281):281–284PubMedGoogle Scholar
  162. Yao EH, Fukuda N et al (2008) Effects of the antioxidative beta-blocker celiprolol on endothelial progenitor cells in hypertensive rats. Am J Hypertens 21(9):1062–1068PubMedGoogle Scholar
  163. Yoshino G, Hirano T et al (1997) Effect of long-term exogenous hyperinsulinemia and fructose or glucose supplementation on triglyceride turnover in rats. Atherosclerosis 129(1):33–39PubMedGoogle Scholar
  164. Zhou Z, Wang J et al (2004) Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 64(14):4699–4702PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • C. P. Vicente
    • 1
    Email author
  • J. A. P. Godoy
    • 1
  • C. C. Werneck
    • 2
  1. 1.Department of Anatomy, Cellular Biology, physiology and Biophysics, Biology Institute CP 6109State University of Campinas – UNICAMPCampinasBrazil
  2. 2.Department of Biochemistry, Biology Institute CP 6109State University of Campinas – UNICAMPCampinasBrazil

Personalised recommendations