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

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.