Atherogenic concentrations of low-density lipoprotein enhance endothelial cell generation of epoxyeicosatrienoic acid products.
To investigate the effects of protracted low-density lipoprotein (LDL) exposure on endothelial cell (EC) epoxyeicosatrienoic acid (EET) generation, human umbilical vein ECs were incubated in atherogenic concentrations of LDL (240 mg cholesterol per deciliter) (LDL-EC). After 4 days' incubation with LDL, EC were stimulated with human thrombin in the presence of 1-[14C]-arachidonic acid. Substantially more EET products were generated by LDL-ECs than by cells not exposed to high levels of LDL (C-EC). Thrombin stimulation caused LDL-EC to produce five- to eightfold more in 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET, with 14,15-EET as the major product. This is the first demonstration, to date, that EETs can be induced in EC. Metapyrone (SKF-525A) markedly inhibited EC EET generation, indicating a role for the cytochrome P-450 enzyme system in human EC arachidonic acid metabolism. One EET product, 14,15-EET, has been found to be chemotactic and to promote adhesion of U937 cells, a human monocytic lymphoma cell line, to EC. Thus, protracted exposure to atherogenic LDL concentrations increases the generation of chemotactic and adhesion factors (ie, 14,15-EET) after thrombin stimulation, possibly through the cytochrome P-450 enzyme system.
Pritchard
K A
KA
Department of Medicine, New York Medical College, Valhalla 10595.
Wong
P Y
PY
Stemerman
M B
MB
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008077:Lipoproteins, LDL; D013917:Thrombin; D015126:8,11,14-Eicosatrienoic Acid