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

doi:10.1096/fj.202201469R

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

FASEB J. 2023 Apr;37(4):e22846. doi: 10.1096/fj.202201469R.

Authors

Nisha Schwarz¹, Sanuja Fernando^{1

2}, Yung-Chih Chen³, Thalia Salagaras¹, Sushma R Rao⁴, Sanuri Liyanage^{1

2}, Anna E Williamson^{1

2}, Deborah Toledo-Flores¹, Catherine Dimasi¹, Timothy J Sargeant⁵, Jim Manavis², Eleanor Eddy³, Peter Kanellakis³, Peter L Thompson⁶, Joanne T M Tan^{1

2}, Marten F Snel⁴, Christina A Bursill^{1

2}, Stephen J Nicholls⁷, Karlheinz Peter³, Peter J Psaltis^{1

2}

Affiliations

¹ Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
² Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
³ Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁴ Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁵ Lifelong Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁶ Faculty of Health and Medical Sciences, Internal Medicine, The University of Western Australia, Perth, Western Australia, Australia.
⁷ Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia.

PMID: 36856983
DOI: 10.1096/fj.202201469R

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 < .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.

Keywords: CD36; atherosclerosis; colchicine; foam cells; inflammasome; tubulin; unstable plaque.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis*
Cardiovascular Diseases*
Carotid Stenosis*
Cholesterol
Colchicine
Foam Cells
Humans
Mice

Substances

oil red O
Colchicine
Cholesterol