KLF2-dependent, shear stress-induced expression of CD59: a novel cytoprotective mechanism against complement-mediated injury in the vasculature.
Complement activation may predispose to vascular injury and atherogenesis. The atheroprotective actions of unidirectional laminar shear stress led us to explore its influence on endothelial cell expression of complement inhibitory proteins CD59 and decay-accelerating factor. Human umbilical vein and aortic endothelial cells were exposed to laminar shear stress (12 dynes/cm(2)) or disturbed flow (+/- 5 dynes/cm(2) at 1Hz) in a parallel plate flow chamber. Laminar shear induced a flow rate-dependent increase in steady-state CD59 mRNA, reaching 4-fold at 12 dynes/cm(2). Following 24-48 h of laminar shear stress, cell surface expression of CD59 was up-regulated by 100%, whereas decay-accelerating factor expression was unchanged. The increase in CD59 following laminar shear was functionally significant, reducing C9 deposition and complement-mediated lysis of flow-conditioned endothelial cells by 50%. Although CD59 induction was independent of PI3-K, ERK1/2 and nitric oxide, an RNA interference approach demonstrated dependence upon an ERK5/KLF2 signaling pathway. In contrast to laminar shear stress, disturbed flow failed to induce endothelial cell CD59 protein expression. Likewise, CD59 expression on vascular endothelium was significantly higher in atheroresistant regions of the murine aorta exposed to unidirectional laminar shear stress, when compared with atheroprone areas exposed to disturbed flow. We propose that up-regulation of CD59 via ERK5/KLF2 activation leads to endothelial resistance to complement-mediated injury and protects from atherogenesis in regions of laminar shear stress.
Kinderlerer
Anne R
AR
Cardiovascular Sciences, Bywaters Center for Vascular Inflammation, National Heart and Lung Institute, Imperial College London, London, UK.
Ali
Faisal
F
Johns
Michael
M
Lidington
Elaine A
EA
Leung
Viola
V
Boyle
Joseph J
JJ
Hamdulay
Shahir S
SS
Evans
Paul C
PC
Haskard
Dorian O
DO
Mason
Justin C
JC
D000818:Animals; D001011:Aorta / Q000293:injuries* / Q000378:metabolism*; D018957:CD59 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D019610:Cytoprotection; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D014470:Umbilical Cord / Q000378:metabolism*; D015854:Up-Regulation
D018957:CD59 Antigens; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases