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Laminar shear stress upregulates the complement-inhibitory protein clusterin : a novel potent defense mechanism

C Urbich1, M Fritzenwanger, A M Zeiher

  • 1Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.

Circulation
|February 2, 2000
PubMed

Insights

Shear stress reduces complement-induced inflammation in endothelial cells by increasing clusterin, a protective protein. This finding may explain how shear stress prevents atherosclerosis development.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Endothelial Cell Biology

Background:

  • The complement system contributes to atherosclerosis pathogenesis.
  • Complement activation in endothelial cells (ECs) triggers a proinflammatory response.
  • Physiological shear stress has protective antiatherosclerotic effects.

Purpose of the Study:

  • To investigate if shear stress counteracts complement-mediated EC activation.
  • To elucidate the molecular mechanisms behind shear stress's protective effects.

Main Methods:

  • ECs were exposed to complement serum (CS) with or without prior laminar shear stress.
  • mRNA and protein expression of inflammatory markers (IL-8, MCP-1) and clusterin were quantified.
  • Clusterin function was assessed using antisense oligonucleotides and overexpression.

Main Results:

  • Complement serum upregulated IL-8 and MCP-1 mRNA in ECs.
  • Laminar shear stress abrogated CS-induced IL-8 release and reduced MCP-1 expression.
  • Shear stress increased clusterin mRNA and protein levels.
  • Clusterin inhibition reversed shear stress's protective effects, while overexpression inhibited EC activation.

Conclusions:

  • Shear stress prevents complement-induced EC inflammation by upregulating clusterin.
  • Increased clusterin expression by shear stress may protect against atherosclerosis by inhibiting complement activation on ECs.
Abstract

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