title: Induction of apoptosis in circulating angiogenic cells by microparticles.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is an autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers of circulating angiogenic cells (CACs). The aim of this study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with reduced numbers of CACs.
  
  
  METHODS
  Apoptosis was quantified by staining for annexin V and measurement of caspase 3 activity. The uptake of microparticles by CACs was determined by fluorescence-activated cell sorting and by fluorescence microscopy. Tritiated arachidonic acid and phosphatidylinositol 3,5-bisphosphate were used to demonstrate the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticle-induced apoptosis of endothelial progenitor cells.
  
  
  RESULTS
  Microparticles derived from activated or apoptotic ECs, the expression of which is strongly increased in the blood of patients with SSc, 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 proapoptotic 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.
  
  
  CONCLUSIONS
  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.
authors: University of Erlangen-Nuremberg, Erlangen, Germany. joerg.distler@uk-erlangen.de
authors: Jörg H W
authors: JH
authors: Distler
authors: Alfiya
authors: A
authors: Akhmetshina
authors: Clara
authors: C
authors: Dees
authors: Astrid
authors: A
authors: Jüngel
authors: Michael
authors: M
authors: Stürzl
authors: Steffen
authors: S
authors: Gay
authors: David S
authors: DS
authors: Pisetsky
authors: Georg
authors: G
authors: Schett
authors: Oliver
authors: O
authors: Distler
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016718:Arachidonic Acid / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology
chemical_list: D017304:Annexin A5; D016718:Arachidonic Acid; D053148:Caspase 3