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KLF‐2‐dependent, shear stress‐induced expression of CD59: a novel cytoprotective mechanism against complement‐mediated injury in the vasculature
Author(s) -
Mason Justin Charles,
Kinderlerer Anne,
Ali Faisal,
Johns Michael,
Leung Viola,
Boyle Joseph,
Evans Paul,
Haskard Dorian O
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.471.2
Subject(s) - cd59 , klf2 , umbilical vein , downregulation and upregulation , complement system , chemistry , nitric oxide , microbiology and biotechnology , decay accelerating factor , endothelial stem cell , endothelium , complement membrane attack complex , immunology , biology , immune system , endocrinology , biochemistry , in vitro , organic chemistry , gene
Complement activation may predispose to vascular injury and atherogenesis. The atheroprotective actions of unidirectional laminar shear stress (LSS) led us to explore its effects on endothelial cell (EC) expression of complement inhibitory proteins CD59 and decay‐accelerating factor (DAF). Human umbilical vein and aortic EC were exposed to LSS (12 dynes/cm 2 ), or disturbed flow (DF) (+/−5 dynes/cm 2 at 1Hz), in a parallel‐plate flow chamber. LSS induced a flow rate‐dependent increase in steady‐state CD59 mRNA, reaching 4‐fold at 12 dynes/cm 2 (p<0.01). Following 24–48h of LSS, cell surface CD59 was upregulated by 100% (p<0.01), while DAF expression was unchanged. The increase in CD59 following LSS was functionally significant, reducing C9 deposition and complement‐mediated lysis of flow‐conditioned EC by 50% (p<0.05). While CD59 induction was independent of PI‐3K, ERK1/2 and nitric oxide, an siRNA approach demonstrated dependence upon an ERK5/KLF2 signalling pathway. In contrast to LSS, DF failed to induce EC CD59 protein expression. Likewise, CD59 expression on vascular endothelium was significantly higher in atheroresistant regions of the murine aorta exposed to unidirectional LSS, when compared to atheroprone areas exposed to DF (p<0.05). We propose that upregulation of CD59 via ERK5/KLF2 activation leads to endothelial resistance to complement‐mediated injury, and protects from atherogenesis in regions of LSS.