Colchicine promotes atherosclerotic plaque stability independently of inflammation

Author:

Li Weizhen,Lin Alexander,Hutton Michael,Dhaliwal Harkirat,Nadel James,Rodor Julie,Tumanov Sergey,Örd Tiit,Hadden Matthew,Mokry Michal,Mol Barend M,Pasterkamp Gerard,Padula Matthew P,Geczy Carolyn L,Ramaswamy Yogambha,Sluimer Judith C,Kaikkonen Minna UORCID,Stocker Roland,Baker Andrew H,Fisher Edward AORCID,Patel Sanjay,Misra AshishORCID

Abstract

AbstractAtherosclerosis is a chronic inflammatory disease which is driven in part by the aberranttrans-differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

Publisher

Cold Spring Harbor Laboratory

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