Colchicine promotes atherosclerotic plaque stability independently of inflammation.
Weizhen LiAlexander LinMichael HuttonHarkirat DhaliwalJames NadelJulie RodorSergey TumanovTiit ÖrdMatthew HaddenMichal MokryBarend M MolGerard PasterkampMatthew P PadulaCarolyn L GeczyYogambha RamaswamyJudith C SluimerMinna U KaikkonenRoland StockerAndrew H BakerEdward A FisherSanjay PatelAshish MisraPublished in: bioRxiv : the preprint server for biology (2023)
Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans -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.
Keyphrases
- coronary artery disease
- vascular smooth muscle cells
- clinical trial
- single cell
- oxidative stress
- cardiovascular disease
- induced apoptosis
- anti inflammatory
- cell therapy
- high resolution
- randomized controlled trial
- adipose tissue
- angiotensin ii
- case report
- type diabetes
- risk assessment
- mass spectrometry
- bone marrow
- mesenchymal stem cells
- endothelial cells
- high density
- adverse drug