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Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE


Chaabane, Chiraz; Heizmann, Claus W; Bochaton-Piallat, Marie-Luce (2015). Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE. BBA - Biochimica et Biophysica Acta, 1853(9):2144-2157.

Abstract

We identified S100A4 as a marker of rhomboid (R) smooth muscle cells (SMCs) in vitro (the synthetic phenotype, typical of intimal SMCs) in the porcine coronary artery and of intimal SMCs in vivo in both pigs and humans. S100A4 is an intracellular Ca(2+) signaling protein and can be secreted; it has extracellular functions via the receptor for advanced glycation end products (RAGE). Our objective was to explore the role of S100A4 in SMC phenotypic change, a phenomenon characteristic of atherosclerotic plaque formation. Transfection of a human S100A4-containing plasmid in spindle-shaped (S) SMCs (devoid of S100A4) led to approximately 10% of S100A4-overexpressing SMCs, S100A4 release, and a transition towards a R-phenotype of the whole SMC population. Furthermore treatment of S-SMCs with S100A4-rich conditioned medium collected from S100A4-transfected S-SMCs induced a transition towards a R-phenotype, which was associated with decreased SMC differentiation markers and increased proliferation and migration by activating the urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). It yielded NF-κB activation in a RAGE-dependent manner. Blockade of extracellular S100A4 in R-SMCs with S100A4 neutralizing antibody induced a transition from R- to S-phenotype, decreased proliferative activity and upregulation of SMC differentiation markers. By contrast, silencing of S100A4 mRNA in R-SMCs did not change the level of extracellular S100A4 or SMC morphology in spite of decreased proliferative activity. Our results show that extracellular S100A4 plays a pivotal role in SMC phenotypic changes. It could be a new target to prevent SMC accumulation during atherosclerosis and restenosis. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

We identified S100A4 as a marker of rhomboid (R) smooth muscle cells (SMCs) in vitro (the synthetic phenotype, typical of intimal SMCs) in the porcine coronary artery and of intimal SMCs in vivo in both pigs and humans. S100A4 is an intracellular Ca(2+) signaling protein and can be secreted; it has extracellular functions via the receptor for advanced glycation end products (RAGE). Our objective was to explore the role of S100A4 in SMC phenotypic change, a phenomenon characteristic of atherosclerotic plaque formation. Transfection of a human S100A4-containing plasmid in spindle-shaped (S) SMCs (devoid of S100A4) led to approximately 10% of S100A4-overexpressing SMCs, S100A4 release, and a transition towards a R-phenotype of the whole SMC population. Furthermore treatment of S-SMCs with S100A4-rich conditioned medium collected from S100A4-transfected S-SMCs induced a transition towards a R-phenotype, which was associated with decreased SMC differentiation markers and increased proliferation and migration by activating the urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). It yielded NF-κB activation in a RAGE-dependent manner. Blockade of extracellular S100A4 in R-SMCs with S100A4 neutralizing antibody induced a transition from R- to S-phenotype, decreased proliferative activity and upregulation of SMC differentiation markers. By contrast, silencing of S100A4 mRNA in R-SMCs did not change the level of extracellular S100A4 or SMC morphology in spite of decreased proliferative activity. Our results show that extracellular S100A4 plays a pivotal role in SMC phenotypic changes. It could be a new target to prevent SMC accumulation during atherosclerosis and restenosis. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2015
Deposited On:30 Sep 2014 15:09
Last Modified:05 Apr 2016 18:23
Publisher:Elsevier
ISSN:0006-3002
Publisher DOI:https://doi.org/10.1016/j.bbamcr.2014.07.022
PubMed ID:25110349
Permanent URL: https://doi.org/10.5167/uzh-98877

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