Modified LDL Decreases the Binding of Prostaglandin E 2, I 2, and E 1 Onto Monocytes in Patients With Peripheral Vascular Disease

Abstract

Abstract Recent data suggest that various eicosanoids including prostaglandins play an important regulatory role in the development of atherosclerotic lesions. Peripheral blood monocytes have been implemented in early atherogenesis because they express receptors specific for modified LDL. In this study we investigated the binding of tritium prostaglandins E 2 ( 3 H-PGE 2 ), E 1 ( 3 H-PGE 1 ) and I 2 ( 3 H-PGI 2 ) onto intact peripheral monocytes isolated from 20 patients (32-71 years) with manifested ischemic peripheral vascular disease stage II according to Fontaine and compared the results with those obtained in 16 healthy volunteers (21-68 years). In control subjects, Scatchard analyses of the binding data indicated a single class of high-affinity binding sites for 3 H-PGE 2 (maximal binding capacity [B max ]=11400±3200 sites/cell; dissociation constant [K d ]=1.3±0.5 nmol/L) and two classes of binding sites for 3 H-PGE 1 (B max1 =11200±4900 sites/cell, K d1 =1.5±0.5 nmol/L; B max2 =47800±6100 sites/cell, K d2 =12.8±5.9 nmol/L) as well as for 3 H-PGI 2 (B max1 =10100±3700 sites/cell, K d1 =1.7 ±0.7 nmol/L; B max2 =81200±5200 sites/cell, K d2 =14.2±6.5 nmol/L). In the patients, an absence of the higher-affinity binding class and significantly ( P <.01) fewer lower-affinity binding sites were found for each ligand (PGE 2 : B max = 6600±3600 sites/cell, K d =12.1±3.2 nmol/L; PGI 2 : B max =6400 ±3100 sites/cell, K d =22.1±8.3; PGE 1 : B max =5300±1700 sites/cell, K d =20.5±7.0 nmol/L). After incubation of monocytes with modified LDL (oxidized LDL or acetylated LDL), the binding of prostaglandins was significantly ( P <.01 to P <.001) decreased, whereas native VLDL, LDL, and HDL did not interfere with prostaglandin binding. Prostaglandin-induced adenosine 3′-5′ cyclic monophosphate (cAMP) formation by monocytes was significantly ( P <.01) lower in patients (the concentrations causing 50% elevation of basal cAMP formation [ED 50 ] were 3.8±2.4 nmol/L for PGE 2 , 6.3±3.5 nmol/L for PGE 1 , and 5.6±4.1 nmol/L for PGI 2 ) than in the control subjects (ED 50 was 1.6±1.2 nmol/L for PGE 2 , 4.8±2.5 nmol/L for PGE 1 , and 3.1±1.4 nmol/L for PGI 2 ). After preincubation with modified LDL, the PG-induced cAMP production by monocytes was remarkably decreased in both patients and control subjects ( P <.05). Our results suggest a direct effect of modified LDL on PGE 2, PGE 1 , and PGI 2 binding onto monocytes by reducing the number of cell surface–expressed receptors available. Modified LDL also reduces the sensitivity of monocytes to prostaglandins, which results in decreased cAMP production. The complex interactions between prostaglandins and lipoproteins may play an important role during atherogenesis.