OXIDIZED LDL-INDUCED LEUKOCYTE-ENDOTHELIUM INTERACTION IN-VIVO INVOLVES THE RECEPTOR FOR PLATELET-ACTIVATING-FACTOR

Leukocyte adhesion and subendothelial emigration, constant hallmarks of early atherogenesis, have been ascribed to the action of oxidized low-density lipoprotein (oxLDL). Using intravital fluorescence microscopy in the skinfold-chamber model in hamsters, we have previously shown that systemic administration of oxLDL stimulates leukocyte adhesion in vivo through a mechanism that depends on the generation and/or action of both leukotrienes and superoxide radicals. On the basis of the fact that oxygen radical-catalyzed peroxidation of phospholipids results in the generation of fragments with short sn2 residues, which besides authentic platelet-activating factor (PAF), activate the receptor for PAF on leukocytes and thereby induce leukocyte adhesion, we asked whether pretreatment of hamsters with a specific PAF receptor antagonist (WEB2170; 1 mg/kg of body weight IV, 10 minutes before oxLDL) attenuates leukocyte adhesion after injection of oxLDL (4 mg/kg of body weight IV, oxidized by 7.5 mumol/L Cu2+ for 18 hours at 37-degrees-C). We demonstrate herein that in contrast to untreated control animals in which oxLDL elicited rolling and adhesion of circulating leukocytes to the endothelium of venules and arterioles, oxLDL-induced leukocyte adhesion was significantly attenuated in WEB2170-pretreated animals. These changes cannot be ascribed to alterations of microhemodynamic parameters and, hence, wall shear conditions. This finding indicates that oxLDL-induced leukocyte/endothelium interaction involves the PAF receptor, which may function both as a receptor for authentic PAF or for PAF-like lipids that are generated in a free radical-catalyzed peroxidation of phospholipids.