PMID- 10653823
OWN - NLM
STAT- MEDLINE
DCOM- 20000218
LR  - 20190623
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 101
IP  - 4
DP  - 2000 Feb 1
TI  - Laminar shear stress upregulates the complement-inhibitory protein clusterin : a 
      novel potent defense mechanism against complement-induced endothelial cell 
      activation.
PG  - 352-5
AB  - 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. METHODS AND 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.
FAU - Urbich, C
AU  - Urbich C
AD  - Molecular Cardiology, Department of Internal Medicine IV, University of 
      Frankfurt, Germany.
FAU - Fritzenwanger, M
AU  - Fritzenwanger M
FAU - Zeiher, A M
AU  - Zeiher AM
FAU - Dimmeler, S
AU  - Dimmeler S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (CLU protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Clusterin)
RN  - 0 (Complement Inactivator Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Interleukin-8)
RN  - 0 (Molecular Chaperones)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 9007-36-7 (Complement System Proteins)
SB  - IM
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics
MH  - Clusterin
MH  - Complement Inactivator Proteins/*biosynthesis/genetics
MH  - Complement System Proteins/*physiology
MH  - Endothelium, Vascular/*physiology
MH  - Gene Expression Regulation/immunology
MH  - Glycoproteins/*biosynthesis/genetics
MH  - Humans
MH  - Interleukin-8/genetics
MH  - *Molecular Chaperones
MH  - RNA, Messenger/genetics
MH  - Recombinant Proteins/biosynthesis
MH  - Stress, Mechanical
MH  - *Transcription, Genetic
MH  - Transfection
MH  - Umbilical Veins
EDAT- 2000/02/02 00:00
MHDA- 2000/02/26 00:00
CRDT- 2000/02/02 00:00
PHST- 2000/02/02 00:00 [pubmed]
PHST- 2000/02/26 00:00 [medline]
PHST- 2000/02/02 00:00 [entrez]
AID - 10.1161/01.cir.101.4.352 [doi]
PST - ppublish
SO  - Circulation. 2000 Feb 1;101(4):352-5. doi: 10.1161/01.cir.101.4.352.