Colchicine promotes atherosclerotic plaque stability independently of inflammation

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

doi:10.1101/2023.10.03.560632

Colchicine promotes atherosclerotic plaque stability independently of inflammation

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

Research output: Working paper › Preprint › Academic

Abstract

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.

Original language	English
Publisher	BioRxiv
Number of pages	22
DOIs	https://doi.org/10.1101/2023.10.03.560632
Publication status	Published - 3 Oct 2023

Publication series

Name	bioRxiv
Publisher	Cold Spring Harbor Laboratory Press
ISSN (Print)	2692-8205

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10.1101/2023.10.03.560632

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Li, W., Lin, A., Hutton, M., Dhaliwal, H., Nadel, J., Rodor, J., Tumanov, S., Örd, T., Hadden, M., Mokry, M., Mol, B. M., Pasterkamp, G., Padula, M. P., Geczy, C. L., Ramaswamy, Y., Sluimer, J. C., Kaikkonen, M. U., Stocker, R., Baker, A. H., ... Misra, A. (2023). Colchicine promotes atherosclerotic plaque stability independently of inflammation. (bioRxiv). BioRxiv. https://doi.org/10.1101/2023.10.03.560632

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title = "Colchicine promotes atherosclerotic plaque stability independently of inflammation",

abstract = "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. ",

author = "Weizhen Li and Alexander Lin and Michael Hutton and Harkirat Dhaliwal and James Nadel and Julie Rodor and Sergey Tumanov and Tiit {\"O}rd and Matthew Hadden and Michal Mokry and Mol, \{Barend M\} and Gerard Pasterkamp and Padula, \{Matthew P\} and Geczy, \{Carolyn L\} and Yogambha Ramaswamy and Sluimer, \{Judith C\} and Kaikkonen, \{Minna U\} and Roland Stocker and Baker, \{Andrew H\} and Fisher, \{Edward A\} and Sanjay Patel and Ashish Misra",

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Li, W, Lin, A, Hutton, M, Dhaliwal, H, Nadel, J, Rodor, J, Tumanov, S, Örd, T, Hadden, M, Mokry, M, Mol, BM, Pasterkamp, G, Padula, MP, Geczy, CL, Ramaswamy, Y, Sluimer, JC, Kaikkonen, MU, Stocker, R, Baker, AH, Fisher, EA, Patel, S & Misra, A 2023 'Colchicine promotes atherosclerotic plaque stability independently of inflammation' bioRxiv, BioRxiv. https://doi.org/10.1101/2023.10.03.560632

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T1 - Colchicine promotes atherosclerotic plaque stability independently of inflammation

AU - Li, Weizhen

AU - Lin, Alexander

AU - Hutton, Michael

AU - Dhaliwal, Harkirat

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AU - Rodor, Julie

AU - Tumanov, Sergey

AU - Örd, Tiit

AU - Hadden, Matthew

AU - Mokry, Michal

AU - Mol, Barend M

AU - Pasterkamp, Gerard

AU - Padula, Matthew P

AU - Geczy, Carolyn L

AU - Ramaswamy, Yogambha

AU - Sluimer, Judith C

AU - Kaikkonen, Minna U

AU - Stocker, Roland

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AU - Misra, Ashish

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N2 - 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.

AB - 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.

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BT - Colchicine promotes atherosclerotic plaque stability independently of inflammation

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ER -

Colchicine promotes atherosclerotic plaque stability independently of inflammation

Abstract

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