Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation

Nisha Schwarz, Sanuja Fernando, Yung Chih Chen, Thalia Salagaras, Sushma R. Rao, Sanuri Liyanage, Anna E. Williamson, Deborah Toledo-Flores, Catherine Dimasi, Timothy J. Sargeant, Jim Manavis, Eleanor Eddy, Peter Kanellakis, Peter L. Thompson, Joanne T.M. Tan, Marten F. Snel, Christina A. Bursill, Stephen J. Nicholls, Karlheinz Peter, Peter J. Psaltis

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

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-1β 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 
Original languageEnglish
Article numbere22846
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume37
Issue number4
DOIs
Publication statusPublished - 1 Apr 2023

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