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Title: HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice
Authors: Theilmeier, G ×
De Geest, Bart
Van Veldhoven, Paul P
Stengel, D
Michiels, C
Lox, M
Landeloos, M
Chapman, M J
Ninio, E
Collen, Desire
Himpens, Bernard
Holvoet, Paul #
Issue Date: Nov-2000
Publisher: The Federation of American Societies for Experimental Biology
Series Title: FASEB Journal vol:14 issue:13 pages:2032-9
Abstract: Macrophage infiltration into the subendothelial space at lesion prone sites is the primary event in atherogenesis. Inhibition of macrophage homing might therefore prevent atherosclerosis. Since HDL levels are inversely correlated with cardiovascular risk, their effect on macrophage homing was assessed in apoE-deficient (apoE-/-) mice. Overexpression of human apolipoprotein AI in apoE-/- mice increased HDL levels 3-fold and reduced macrophage accumulation in an established assay of leukocyte homing to aortic root endothelium 3.2-fold (P<0.005). This was due to reduced in vivo betaVLDL oxidation, reduced betaVLDL triggered endothelial cytosolic Ca2+ signaling through PAF-like bioactivity, lower ICAM-1 and VCAM-1 expression, and diminished ex vivo leukocyte adhesion. Adenoviral gene transfer of human PAF-acetylhydrolase (PAF-AH) in apoE-/- mice increased PAF-AH activity 1.5-fold (P<0.001), reduced betaVLDL-induced ex vivo macrophage adhesion 3.5-fold (P<0.01), and reduced in vivo macrophage homing 2.6-fold (P<0.02). These inhibitory effects were observed in the absence of increased HDL cholesterol levels. In conclusion, HDL reduces macrophage homing to endothelium by reducing oxidative stress via its associated PAF-AH activity. This protective mechanism is independent of the function of HDL as cholesterol acceptor. Modulation of lipoprotein oxidation by PAF-AH may prevent leukocyte recruitment to the vessel wall, a key feature in atherogenesis.
URI: 
ISSN: 0892-6638
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Atherosclerosis and Metabolism (-)
Laboratory of Molecular and Cellular Signaling
Laboratory of Lipid Biochemistry and Protein Interactions
× corresponding author
# (joint) last author

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