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Neutralization of S100A4 Induces Stabilization of Atherosclerotic Plaques: Role of Smooth Muscle Cells

Overview

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2020 Nov 2

PMID 33135065

Citations 9

Authors

Authors

Antonija Sakic

Chiraz Chaabane

Noona Ambartsumian

Jorg Klingelhofer

Sylvain Lemeille

Brenda R Kwak

Mariam Grigorian

Marie-Luce Bochaton-Piallat

Affiliations

Affiliations

Soon will be listed here.

Abstract

Aims: During atherosclerosis, smooth muscle cells (SMCs) accumulate in the intima where they switch from a contractile to a synthetic phenotype. From porcine coronary artery, we isolated spindle-shaped (S) SMCs exhibiting features of the contractile phenotype and rhomboid (R) SMCs typical of the synthetic phenotype. S100A4 was identified as a marker of R-SMCs in vitro and intimal SMCs, in pig and man. S100A4 exhibits intra- and extracellular functions. In this study, we investigated the role of extracellular S100A4 in SMC phenotypic transition.

Methods And Results: S-SMCs were treated with oligomeric recombinant S100A4 (oS100A4), which induced nuclear factor (NF)-κB activation. Treatment of S-SMCs with oS100A4 in combination with platelet-derived growth factor (PDGF)-BB induced a complete SMC transition towards a pro-inflammatory R-phenotype associated with NF-κB activation, through toll-like receptor-4. RNA sequencing of cells treated with oS100A4/PDGF-BB revealed a strong up-regulation of pro-inflammatory genes and enrichment of transcription factor binding sites essential for SMC phenotypic transition. In a mouse model of established atherosclerosis, neutralization of extracellular S100A4 decreased area of atherosclerotic lesions, necrotic core, and CD68 expression and increased α-smooth muscle actin and smooth muscle myosin heavy chain expression.

Conclusion: We suggest that the neutralization of extracellular S100A4 promotes the stabilization of atherosclerotic plaques. Extracellular S100A4 could be a new target to influence the evolution of atherosclerotic plaques.

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