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Induction of apoptosis in circulating angiogenic cells by microparticles


Distler, J H W; Akhmetshina, A; Dees, C; Jüngel, A; Stürzl, M; Gay, S; Pisetsky, D S; Schett, G; Distler, O (2011). Induction of apoptosis in circulating angiogenic cells by microparticles. Arthritis and Rheumatism, 63(7):2067-2077.

Abstract

PURPOSE.: Systemic sclerosis (SSc) is a autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers circulating angiogenic cells (CACs). The aim of the present study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with the reduced numbers of CACs. METHODS.: Apoptosis was quantified by staining for annexin V and measurement of the caspase 3 activity. The uptake of microparticles by CACs was determined by FACS and by fluorescence microscopy. Tritiated arachidonic acid and PtdIns3,5BP were used to demonstrated the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticles induced apoptosis of EPCs. RESULTS.: Microparticles derived from activated or apoptotic ECs, which are strongly increased in the blood of SSc patients, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs and purified arachidonic acid mimics the pro-apoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase and inhibition of acid sphingomyelinase prevents microparticle induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. CONCLUSION.: The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs and impaired formation of new vessels in SSc.

PURPOSE.: Systemic sclerosis (SSc) is a autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers circulating angiogenic cells (CACs). The aim of the present study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with the reduced numbers of CACs. METHODS.: Apoptosis was quantified by staining for annexin V and measurement of the caspase 3 activity. The uptake of microparticles by CACs was determined by FACS and by fluorescence microscopy. Tritiated arachidonic acid and PtdIns3,5BP were used to demonstrated the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticles induced apoptosis of EPCs. RESULTS.: Microparticles derived from activated or apoptotic ECs, which are strongly increased in the blood of SSc patients, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs and purified arachidonic acid mimics the pro-apoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase and inhibition of acid sphingomyelinase prevents microparticle induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. CONCLUSION.: The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs and impaired formation of new vessels in SSc.

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20 citations in Web of Science®
23 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:23 May 2011 13:35
Last Modified:05 Apr 2016 14:55
Publisher:Wiley-Blackwell
ISSN:0004-3591
Publisher DOI:10.1002/art.30361
PubMed ID:21437873

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