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.
Institute for Surgical Research, University of Munich, FRG.
H A
HA
Lehr
J
J
Seemüller
C
C
Hübner
M D
MD
Menger
K
K
Messmer
D000818:Animals; D002450:Cell Communication; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology*; D007962:Leukocytes / Q000166:cytology*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology*; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D008856:Microscopy, Fluorescence / Q000379:methods; D010084:Oxidation-Reduction; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled
D008077:Lipoproteins, LDL; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor