MODIFIED LDL DECREASES THE BINDING OF PROSTAGLANDIN E-2, I-2, AND E-1ONTO MONOCYTES IN PATIENTS WITH PERIPHERAL VASCULAR-DISEASE

Recent data suggest that various eicosanoids including prostaglandins play an important regulatory role in the development of atheroscleroti c lesions. Peripheral blood monocytes have been implemented in early a therogenesis because they express receptors specific for modified LDL. In this study we investigated the binding of tritium prostaglandins E -2 (H-3-PGE(2)), E-1 (H-3-PGE(1)) and I-2 (H-3-PGI(2)) onto intact per ipheral monocytes isolated from 20 patients (32-71 years) with manifes ted ischemic peripheral vascular disease stage II according to Fontain e and compared the results with those obtained in 16 healthy volunteer s (21-68 years). In control subjects, Scatchard analyses of the bindin g data indicated a single class of high-affinity binding sites for H-3 -PGE(2) (maximal binding capacity [B-max]=11400+/-3200 sites/cell; dis sociation constant [K-d]=1.3+/-0.5 nmol/L) and two classes of binding sites for H-3-PGE(1) (B-max1=11200+/-4900 sites/cell, K-d1=1.5+/-0.5 n mol/L; B-max2=47800+/-6100 sites/cell, K-d2=12.8+/-5.9 nmol/L) as well as for H-3-PGI(2) (B-max1=10100+/-3700 sites/cell, k(d1)=1.7+/-0.7 nm ol/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 signific antly (P<.01) fewer lower-affinity binding sites were found for each l igand (PGE(2): B-max= 6600+/-3600 sites/cell, K-d=12.1+/-3.2 nmol/L; P GI(2): B-max=6400+/-3100 sites/cell, K-d=22.1+/-8.3; PGE(1): B-max=530 0+/-1700 sites/cell, K-d=20.5+/-7.0 nmol/L). After incubation of monoc ytes with modified LDL (oxidized LDL or acetylated LDL), the binding o f prostaglandins was significantly (P<.01 to P<.001) decreased, wherea s native VLDL, LDL, and HDL did not interfere with prostaglandin bindi ng. Prostaglandin-induced adenosine 3'-5' cyclic monophosphate (cAMP) formation by monocytes was significantly (P<.01) lower in patients (th e concentrations causing 50% elevation of basal cAMP formation [ED50] 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 (ED50, was 1.6/-1.2 nmol/L for PGE(2), 4.8+/-2.5 nmol/L for PGE(1), and 3.1+/-1.4 nm ol/L for PGI(2)). After preincubation with modified LDL, the PG-induce d cAMP production by monocytes was remarkably decreased in both patien ts and control subjects (P<.05). Our results suggest a direct effect o f modified LDL on PGE(2), PGE(1), and PGI(2) binding onto monocytes by reducing the number of cell surface-expressed receptors available. Mo dified 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 du ring atherogenesis.