Neutralization of S100A4 induces stabilization of atherosclerotic plaques: role of smooth muscle cells.
Cardiovasc Res
; 118(1): 141-155, 2022 01 07.
Article
em En
| MEDLINE
| ID: mdl-33135065
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças da Aorta
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Miócitos de Músculo Liso
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Aterosclerose
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Anticorpos Neutralizantes
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Placa Aterosclerótica
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Proteína A4 de Ligação a Cálcio da Família S100
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Músculo Liso Vascular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Suíça