Download PDF
Thromb Haemost 2018; 118(07): 1329-1339
DOI: 10.1055/s-0038-1657753
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Chondroitin Sulphate Attenuates Atherosclerosis in ApoE Knockout Mice Involving Cellular Regulation of the Inflammatory Response

Pedro Melgar-Lesmes
1   Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
2   Department of Biomedicine, Fundació Clínic per a la Recerca Biomèdica, University of Barcelona, Barcelona, Spain
,
Alvaro Sánchez-Herrero
1   Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
,
Ferran Lozano-Juan
1   Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
,
Jose María de la Torre Hernández
3   Hospital Marqués de Valdecilla University Hospital, Universidad de Cantabria, Santander, Spain
,
Eulàlia Montell
4   Pre-Clinical R&D Area, Bioibérica S.A.U., Barcelona, Spain
,
Wladimiro Jiménez
5   Biochemistry and Molecular Genetics Service, Department of Biomedicine, Hospital Clínic Universitari, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
,
Elazer R. Edelman
1   Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
6   Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Mercedes Balcells
1   Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
7   Department of Biological Engineering, IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain
› Author Affiliations Funding This work was supported by a grant from Spanish Ministerium of Economy (SAF2013–43302-R) and by Bioibérica and Fundacio Empreses IQS to M.B.; National Institutes of Health (R01 GM 49039) to E.R.E.; Ministerio de Economia y Competitividad (SAF2015–64126-R) to W.J.; European Association for the Study of Liver (EASL), Generalitat de Catalunya (PERIS SLT002/16/00341) and Beatriu de Pinos Program 2016 (BP-00236) to P.M.-L.
Further Information

Publication History

26 February 2018

23 April 2018

Publication Date:
06 June 2018 (online)

Also available at
    Permissions and Reprints

Abstract

Chondroitin sulphate (CS) has long been used to treat osteoarthritis. Some investigations have also shown that the treatment with CS could reduce coronary events in patients with heart disease but no studies have identified the mechanistic role of these therapeutic effects. We aimed to investigate how the treatment with CS can interfere with the progress of atherosclerosis. The aortic arch, thoracic aorta and serum were obtained from apolipoprotein E (ApoE) knockout mice fed for 10 weeks with high-fat diet and then treated with CS (300 mg/kg, n = 15) or vehicle (n = 15) for 4 weeks. Atheromatous plaques were highlighted in aortas with Oil Red staining and analysed by microscopy. ApoE knockout mice treated with CS exhibited attenuated atheroma lesion size by 68% as compared with animals receiving vehicle. Serum lipids, glucose and C-reactive protein were not affected by treatment with CS. To investigate whether CS locally affects the inflamed endothelium or the formation of foam cells in plaques, human endothelial cells and monocytes were stimulated with tumour necrosis factor α or phorbol myristate acetate in the presence or absence of CS. CS reduced the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and ephrin-B2 and improved the migration of inflamed endothelial cells. CS inhibited foam cell formation in vivo and concomitantly CD36 and CD146 expression and oxidized low-density lipoprotein uptake and accumulation in cultured activated human monocytes and macrophages. Reported cardioprotective effects of CS may arise from modulation of pro-inflammatory activation of endothelium and monocytes and foam cell formation.

Keywords

atherosclerosis - inflammation - chondroitin sulphate - immunology - vascular biology

Supplementary Material

 

  • References

  • 1 Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009; 6 (06) 399-409
    CrossrefPubMedSearch in Google Scholar
  • 2 Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol 2017; 174 (20) 3496-3513
    CrossrefPubMedSearch in Google Scholar
  • 3 McKellar GE, McCarey DW, Sattar N, McInnes IB. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol 2009; 6 (06) 410-417
    CrossrefPubMedSearch in Google Scholar
  • 4 Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res 2015; 116 (02) 307-311
    CrossrefPubMedSearch in Google Scholar
  • 5 Libby P. Inflammation in atherosclerosis. Nature 2002; 420 (6917): 868-874
    CrossrefPubMedSearch in Google Scholar
  • 6 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6 (07) 508-519
    CrossrefPubMedSearch in Google Scholar
  • 7 Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010; 7 (02) 77-86
    CrossrefPubMedSearch in Google Scholar
  • 8 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86 (02) 515-581
    CrossrefPubMedSearch in Google Scholar
  • 9 du Souich P, García AG, Vergés J, Montell E. Immunomodulatory and anti-inflammatory effects of chondroitin sulphate. J Cell Mol Med 2009; 13 (8A): 1451-1463
    CrossrefPubMedSearch in Google Scholar
  • 10 Tan GK, Tabata Y. Chondroitin-6-sulfate attenuates inflammatory responses in murine macrophages via suppression of NF-κB nuclear translocation. Acta Biomater 2014; 10 (06) 2684-2692
    CrossrefPubMedSearch in Google Scholar
  • 11 Melgar-Lesmes P, Garcia-Polite F, Del-Rey-Puech P. , et al. Treatment with chondroitin sulfate to modulate inflammation and atherogenesis in obesity. Atherosclerosis 2016; 245: 82-87
    CrossrefPubMedSearch in Google Scholar
  • 12 Morrison LM. Response of ischemic heart disease to chondroitin sulfate-A. J Am Geriatr Soc 1969; 17 (10) 913-923
    CrossrefPubMedSearch in Google Scholar
  • 13 Morrison LM, Enrick N. Coronary heart disease: reduction of death rate by chondroitin sulfate A. Angiology 1973; 24 (05) 269-287
    CrossrefPubMedSearch in Google Scholar
  • 14 Nakazawa K, Murata K. Comparative study of the effects of chondroitin sulfate isomers on atherosclerotic subjects. Z Alternsforsch 1979; 34 (02) 153-159
    PubMedSearch in Google Scholar
  • 15 de Abajo FJ, Gil MJ, García Poza P. , et al. Risk of nonfatal acute myocardial infarction associated with non-steroidal antiinflammatory drugs, non-narcotic analgesics and other drugs used in osteoarthritis: a nested case-control study. Pharmacoepidemiol Drug Saf 2014; 23 (11) 1128-1138
    CrossrefPubMedSearch in Google Scholar
  • 16 Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116 (16) 1832-1844
    CrossrefPubMedSearch in Google Scholar
  • 17 Ronca F, Palmieri L, Panicucci P, Ronca G. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 1998; 6 (Suppl A): 14-21
    CrossrefPubMedSearch in Google Scholar
  • 18 Marcovecchio PM, Thomas GD, Mikulski Z. , et al. Scavenger receptor CD36 directs nonclassical monocyte patrolling along the endothelium during early atherogenesis. Arterioscler Thromb Vasc Biol 2017; 37 (11) 2043-2052
    CrossrefPubMedSearch in Google Scholar
  • 19 Luo Y, Duan H, Qian Y. , et al. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res 2017; 27 (03) 352-372
    CrossrefPubMedSearch in Google Scholar
  • 20 Ramos-Arellano LE, Muñoz-Valle JF, De la Cruz-Mosso U, Salgado-Bernabé AB, Castro-Alarcón N, Parra-Rojas I. Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects. BMC Cardiovasc Disord 2014; 14: 54
    CrossrefPubMedSearch in Google Scholar
  • 21 Di Pietro N, Formoso G, Pandolfi A. Physiology and pathophysiology of oxLDL uptake by vascular wall cells in atherosclerosis. Vascul Pharmacol 2016; 84: 1-7
    CrossrefPubMedSearch in Google Scholar
  • 22 Wu MY, Li CJ, Hou MF, Chu PY. New insights into the role of inflammation in the pathogenesis of atherosclerosis. Int J Mol Sci 2017; 18 (10) E2034
    CrossrefPubMedSearch in Google Scholar
  • 23 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
    CrossrefPubMedSearch in Google Scholar
  • 24 Martorell J, Santomá P, Kolandaivelu K. , et al. Extent of flow recirculation governs expression of atherosclerotic and thrombotic biomarkers in arterial bifurcations. Cardiovasc Res 2014; 103 (01) 37-46
    CrossrefPubMedSearch in Google Scholar
  • 25 Boesten LS, Zadelaar AS, van Nieuwkoop A. , et al. Tumor necrosis factor-alpha promotes atherosclerotic lesion progression in APOE*3-Leiden transgenic mice. Cardiovasc Res 2005; 66 (01) 179-185
    CrossrefPubMedSearch in Google Scholar
  • 26 Hsu HY, Twu YC. Tumor necrosis factor-alpha -mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage. J Biol Chem 2000; 275 (52) 41035-41048
    CrossrefPubMedSearch in Google Scholar
  • 27 Gimbrone Jr MA, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 2013; 22 (01) 9-15
    CrossrefPubMedSearch in Google Scholar
  • 28 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27 (11) 2292-2301
    CrossrefPubMedSearch in Google Scholar
  • 29 Braun J, Hoffmann SC, Feldner A. , et al. Endothelial cell ephrinB2-dependent activation of monocytes in arteriosclerosis. Arterioscler Thromb Vasc Biol 2011; 31 (02) 297-305
    CrossrefPubMedSearch in Google Scholar
  • 30 Sainson RC, Johnston DA, Chu HC. , et al. TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood 2008; 111 (10) 4997-5007
    CrossrefPubMedSearch in Google Scholar
  • 31 Robbins CS, Hilgendorf I, Weber GF. , et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013; 19 (09) 1166-1172
    CrossrefPubMedSearch in Google Scholar
  • 32 Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest 2009; 119 (01) 136-145
    PubMedSearch in Google Scholar
  • 33 Bardin N, Blot-Chabaud M, Despoix N. , et al. CD146 and its soluble form regulate monocyte transendothelial migration. Arterioscler Thromb Vasc Biol 2009; 29 (05) 746-753
    CrossrefPubMedSearch in Google Scholar