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

Pedro Melgar-Lesmes; Alvaro Sánchez-Herrero; Ferran Lozano-Juan; Jose María de la Torre Hernández; Eulàlia Montell; Wladimiro Jiménez; Elazer R. Edelman; Mercedes Balcells

doi:10.1055/s-0038-1657753

Thrombosis and Haemostasis, Table of Contents

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

¹Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

²Department of Biomedicine, Fundació Clínic per a la Recerca Biomèdica, University of Barcelona, Barcelona, Spain

,

Alvaro Sánchez-Herrero

¹Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

,

Ferran Lozano-Juan

¹Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

,

Jose María de la Torre Hernández

³Hospital Marqués de Valdecilla University Hospital, Universidad de Cantabria, Santander, Spain

,

Eulàlia Montell

⁴Pre-Clinical R&D Area, Bioibérica S.A.U., Barcelona, Spain

,

Wladimiro Jiménez

⁵Biochemistry and Molecular Genetics Service, Department of Biomedicine, Hospital Clínic Universitari, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain

,

Elazer R. Edelman

¹Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

⁶Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

,

Mercedes Balcells

¹Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

⁷Department of Biological Engineering, IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain

› Author Affiliations

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

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References

References
1 Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009; 6 (06) 399-409
2 Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol 2017; 174 (20) 3496-3513
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
4 Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res 2015; 116 (02) 307-311
5 Libby P. Inflammation in atherosclerosis. Nature 2002; 420 (6917): 868-874
6 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6 (07) 508-519
7 Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010; 7 (02) 77-86
8 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86 (02) 515-581
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
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
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
12 Morrison LM. Response of ischemic heart disease to chondroitin sulfate-A. J Am Geriatr Soc 1969; 17 (10) 913-923
13 Morrison LM, Enrick N. Coronary heart disease: reduction of death rate by chondroitin sulfate A. Angiology 1973; 24 (05) 269-287
14 Nakazawa K, Murata K. Comparative study of the effects of chondroitin sulfate isomers on atherosclerotic subjects. Z Alternsforsch 1979; 34 (02) 153-159
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
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
17 Ronca F, Palmieri L, Panicucci P, Ronca G. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 1998; 6 (Suppl A): 14-21
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
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
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
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
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
23 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
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
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
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
27 Gimbrone Jr MA, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 2013; 22 (01) 9-15
28 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27 (11) 2292-2301
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
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
31 Robbins CS, Hilgendorf I, Weber GF. , et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013; 19 (09) 1166-1172
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
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

Supplementary Material

Supplementary Material