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Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.
Schwarz, Nisha; Fernando, Sanuja; Chen, Yung-Chih; Salagaras, Thalia; Rao, Sushma R; Liyanage, Sanuri; Williamson, Anna E; Toledo-Flores, Deborah; Dimasi, Catherine; Sargeant, Timothy J; Manavis, Jim; Eddy, Eleanor; Kanellakis, Peter; Thompson, Peter L; Tan, Joanne T M; Snel, Marten F; Bursill, Christina A; Nicholls, Stephen J; Peter, Karlheinz; Psaltis, Peter J.
Afiliación
  • Schwarz N; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Fernando S; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Chen YC; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Salagaras T; Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
  • Rao SR; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Liyanage S; Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Williamson AE; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Toledo-Flores D; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Dimasi C; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Sargeant TJ; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Manavis J; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Eddy E; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Kanellakis P; Lifelong Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Thompson PL; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Tan JTM; Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
  • Snel MF; Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
  • Bursill CA; Faculty of Health and Medical Sciences, Internal Medicine, The University of Western Australia, Perth, Western Australia, Australia.
  • Nicholls SJ; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Peter K; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Psaltis PJ; Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
FASEB J ; 37(4): e22846, 2023 04.
Article en En | MEDLINE | ID: mdl-36856983
Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Estenosis Carotídea / Aterosclerosis Límite: Animals / Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Estenosis Carotídea / Aterosclerosis Límite: Animals / Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos