Pedro Melgar-Lesmes1, Fernando Garcia-Polite2, Paula Del-Rey-Puech2, Elisabet Rosas2, Juliana L Dreyfuss3, Eulàlia Montell4, Josep Vergés4, Elazer R Edelman5, Mercedes Balcells2. 1. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: pedroml@mit.edu. 2. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Bioengineering Department, Institut Químic de Sarrià, Ramon Llull Univ, Barcelona, Spain. 3. Federal University of São Paulo, Escola Paulista de Medicina, Department of Health Informatics, São Paulo, Brazil. 4. Pre-Clinical R&D Area, Pharmascience Division, Bioibérica SA, Barcelona, Spain. 5. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Abstract
BACKGROUND AND AIMS: Osteoarthritic patients treated with high doses of chondroitin sulfate (CS) have a lower incidence of coronary heart disease--but the mechanistic aspects of these beneficial effects of CS remain undefined. We examined how CS treatment affects the formation of atheroma via interaction with endothelial cells and monocytes. METHODS: We characterized arterial atheromatous plaques by multiphoton microscopy and serum pro-inflammatory cytokines by immunoenzymatic techniques in obese mice receiving CS (1 g/kg/day, i.p.) or vehicle for 6 days. Effects of CS on signaling pathways, cytokine secretion and macrophage migration were evaluated in cultures of human coronary endothelial cells and in a monocyte cell line stimulated with TNF-α by Western blot, immunoenzymatic techniques and transwell migration assays. RESULTS: Treatment of obese mice with CS reduced the extension of foam cell coverage in atheromatous plaques of arterial bifurcations by 62.5%, the serum concentration of IL1β by 70%, TNF-α by 82% and selected chemokines by 25-35%. Cultures of coronary endothelial cells and monocytes stimulated with TNF-α secreted less pro-inflammatory cytokines in the presence of CS (P < 0.01). CS reduced the activation of the TNF-α signaling pathway in endothelial cells (pErk 36% of reduction, and NFκB 33% of reduction), and the migration of activated monocytes to inflamed endothelial cells in transwells (81 ± 6 vs. 13 ± 2, P < 0.001). CONCLUSIONS: CS interferes with the pro-inflammatory activation of monocytes and endothelial cells driven by TNF-α thus reducing the propagation of inflammation and preventing the formation of atherosclerotic plaques.
BACKGROUND AND AIMS: Osteoarthritic patients treated with high doses of chondroitin sulfate (CS) have a lower incidence of coronary heart disease--but the mechanistic aspects of these beneficial effects of CS remain undefined. We examined how CS treatment affects the formation of atheroma via interaction with endothelial cells and monocytes. METHODS: We characterized arterial atheromatous plaques by multiphoton microscopy and serum pro-inflammatory cytokines by immunoenzymatic techniques in obesemice receiving CS (1 g/kg/day, i.p.) or vehicle for 6 days. Effects of CS on signaling pathways, cytokine secretion and macrophage migration were evaluated in cultures of human coronary endothelial cells and in a monocyte cell line stimulated with TNF-α by Western blot, immunoenzymatic techniques and transwell migration assays. RESULTS: Treatment of obesemice with CS reduced the extension of foam cell coverage in atheromatous plaques of arterial bifurcations by 62.5%, the serum concentration of IL1β by 70%, TNF-α by 82% and selected chemokines by 25-35%. Cultures of coronary endothelial cells and monocytes stimulated with TNF-α secreted less pro-inflammatory cytokines in the presence of CS (P < 0.01). CS reduced the activation of the TNF-α signaling pathway in endothelial cells (pErk 36% of reduction, and NFκB 33% of reduction), and the migration of activated monocytes to inflamed endothelial cells in transwells (81 ± 6 vs. 13 ± 2, P < 0.001). CONCLUSIONS:CS interferes with the pro-inflammatory activation of monocytes and endothelial cells driven by TNF-α thus reducing the propagation of inflammation and preventing the formation of atherosclerotic plaques.
Authors: S Matthijs Boekholdt; Ron J G Peters; C Erik Hack; Nicholas E Day; Robert Luben; Sheila A Bingham; Nicholas J Wareham; Pieter H Reitsma; Kay-Tee Khaw Journal: Arterioscler Thromb Vasc Biol Date: 2004-06-03 Impact factor: 8.311
Authors: Francisco J de Abajo; Miguel J Gil; Patricia García Poza; Verónica Bryant; Belén Oliva; Julia Timoner; Luis A García-Rodríguez Journal: Pharmacoepidemiol Drug Saf Date: 2014-04-01 Impact factor: 2.890
Authors: Mario Lopez-Moya; Pedro Melgar-Lesmes; Kumaran Kolandaivelu; Jose María de la Torre Hernández; Elazer R Edelman; Mercedes Balcells Journal: Biomacromolecules Date: 2018-03-20 Impact factor: 6.988
Authors: Pedro Melgar-Lesmes; Alvaro Sánchez-Herrero; Ferran Lozano-Juan; Jose María de la Torre Hernández; Eulàlia Montell; Wladimiro Jiménez; Elazer R Edelman; Mercedes Balcells Journal: Thromb Haemost Date: 2018-06-06 Impact factor: 5.249