Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet-activating factor.

Abstract

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 /unol/L Cu J+ for 18 hours at 3TC). 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-Iike lipids that are generated in a free radical-catalyzed peroxidation of phospholipids. In vitro and in vivo experiments have demonstrated that oxLDL induces the chemotactic accumulation and adhesion of leukocytes to endothelial cells. 58 Both the peroxidative modification of LDL 910 and the stimulation of leukocyte adhesion by oxLDL 11 can be inhibited by superoxide dismutase (SOD), thus suggesting that these events involve a superoxide radical-dependent peroxidation of LDL and membrane phospholipids.Uncontrolled oxygen radical-catalyzed peroxidation of phospholipids results in the generation of numerous fragmented phospholipids, some of which activate leu-

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…7). Acyl-alkyl phosphatidylcholines (PC ae) are platelet activating factor (PAF) mimetics that can be ligands or potent agonists of the PAF receptor (79,80). PAF stimulates inflammatory responses and mucin production in respiratory epithelial cells FIG.…”

“…7). In other systems, these molecules play important roles in mucous production, actin polymerization, and host signaling (77)(78)(79)(80).…”

Oxidized Low-Density Lipoprotein Downregulates Endothelial Basic Fibroblast Growth Factor Through a Pertussis Toxin-Sensitive G-Protein Pathway

“…WEB 2086 and WEB 2170, both PAFR antagonists of pyrrolothiazole-derivative origin, have been shown to attenuate various oxLDL or MM-LDL bioactivities, such as monocyte-EC adhesion and smooth muscle cell proliferation. 15,17,32 The oxLDL effects may also be blocked by structurally different PAFR antagonists, such as L659,989, a naturally occurring compound. 32 Whereas the oxLDL effects were prevented by WEB 2086, PAF itself failed to elicit oxLDL-like effects.…”

Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

“…Leukocyte/platelet aggregates, defined as a minimum of three leukocytes per aggregate, tumbling through microvessels within a 30-s observation period were counted in four to six venules per observation window before and at defined times after smoking. When the effect of a PAF receptor antagonist (WEB 2170) was to be examined, animals were given 1 mg/kg body wt i.v., 10 min before smoke exposure (36). Leukocyte-platelet aggregates were isolated from EDTA-anticoagulated blood, fixed, and stained for analysis by electron microscopy as before (37).…”