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* Center for Molecular and Vascular Biology and
Department of Pharmacology, KU Leuven, B-3000 Leuven, Belgium;
Laboratoire de Biochimie et Biologie Cellulaire, FUNDP;
§ INSERM Unité 321, Hôpital de la Pitié, Paris, France; and
¶ Department of Physiology, KU Leuven, B-3000 Leuven, Belgium
1Correspondence: Center for Experimental Surgery and Anesthesiology-CEHA, Onderwijs en Navorsing, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: paul.holvoet{at}med.kuleuven.ac.be
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 ßVLDL oxidation, reduced ßVLDL 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 ßVLDL-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.—Theilmeier, G., De Geest, B., Van Veldhoven, P. P., Stengel, D., Michiels, C., Lox, M., Landeloos, M., Chapman, M. J., Ninio, E., Collen, D., Himpens, B., Holvoet, P. HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice.
Key Words: atherosclerosis • lipoproteins • leukocytes • cell adhesion molecules • signal transduction
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