title: Laminar shear stress upregulates the complement-inhibitory protein clusterin : a novel potent defense mechanism against complement-induced endothelial cell activation.
abstract: BACKGROUND
  The complement system is implicated in the pathogenesis of atherosclerosis. Complement has been shown to activate endothelial cells (ECs) by inducing a proinflammatory response. Physiological levels of shear stress exert potent antiatherosclerotic effects. Therefore, we investigated whether shear stress antagonizes the effects of complement on ECs.
  
  
  RESULTS
  Incubation of ECs with nonlytic concentrations of complement serum (CS: 0.2 U/mL for 6 hours) resulted in an upregulation of interleukin-8 (IL-8) (165+/-12%) and monocyte chemoattractant protein-1 (MCP-1) mRNA expression (267+/-34%). Preexposure of ECs for 18 hours with laminar shear stress (15 dyne/cm(2)) abrogated CS-induced IL-8 release to 106+/-10% (P<0.001) and reduced CS-induced MCP-1 expression (170+/-31%; P<0.05). To examine the mechanism of the protective effect of shear stress, expression of the complement-inhibitory protein clusterin was analyzed under shear exposure. Shear stress increased clusterin mRNA (225+/-76%, 6 hours) and protein expression (164+/-22%, 18 hours). Specific inhibition of clusterin by transfection with antisense oligonucleotides reversed the protective effect of shear stress on CS-induced MCP-1 and IL-8 upregulation (P<0.05 versus sense-transfected cells). Moreover, clusterin overexpression inhibited CS-induced EC activation.
  
  
  CONCLUSIONS
  Shear stress abrogates the complement-induced proinflammatory response of ECs by upregulation of the complement-inhibitory protein clusterin. Upregulation of clusterin may contribute to the potent antiatherosclerotic effects of shear stress by preventing endothelial activation through the complement cascade.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Urbich
authors.forename: M
authors.initials: M
authors.lastname: Fritzenwanger
authors.forename: A M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: S
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics; D003165:Complement System Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D018832:Molecular Chaperones; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D014162:Transfection; D014471:Umbilical Veins
chemical_list: C495242:CLU protein, human; D018932:Chemokine CCL2; D051152:Clusterin; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D016209:Interleukin-8; D018832:Molecular Chaperones; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003165:Complement System Proteins