Synthesis of dihomoprostaglandins from adrenic acid (7,10,13,16-docosatetraenoic acid) by human endothelial cells.
Human umbilical vein endothelial cells were found to contain adrenic acid (22:4) in their cellular lipids. Since this fatty acid may be metabolized by cyclooxygenase in the kidney, the metabolism of adrenic acid was studied in endothelial cell cultures. [14C]Adrenic acid was metabolized to several more polar metabolites. Two of these metabolites co-migrated on HPLC with 1 alpha,1 beta-dihomo-8-ketoprostaglandin F1 alpha (the metabolite of 1 alpha, 1 beta-dihomoprostaglandin I2) and 1 alpha,1 beta-dihomoprostaglandin E2. Indomethacin (10(-5) M) inhibited the synthesis of these metabolites. When cells were treated with adrenic acid (3 X 10(-5) M), a peak that co-migrated with dihomo-8-ketoprostaglandin F1 alpha was detected by radioimmunoassay using an antiserum directed against 6-ketoprostaglandin F1 alpha. The presence of dihomo-8-ketoprostaglandin F1 alpha was confirmed by gas chromatography-mass spectrometry. Immunoreactive peaks that co-migrated with dihomoprostaglandins E2 and F2 alpha were identified with antisera against prostaglandin E2 and prostaglandin F2 alpha, respectively. [14C]Arachidonic acid was metabolized to [14C]prostaglandin F2 alpha, 6-keto[14C]prostaglandin F1 alpha, and [14C]prostaglandin E2. Similar results were found with unlabelled arachidonic acid using specific antisera. When the two fatty acids were combined, adrenic acid reduced the metabolism of arachidonic acid. The culture media from endothelial cells inhibited thrombin-induced platelet aggregation, an effect blocked by aspirin. The inhibitory activity of the media was enhanced when arachidonic acid was added to the cells, but it was reduced by adrenic acid. Both prostaglandin I2 and dihomoprostaglandin I2 inhibited platelet aggregation, but prostaglandin I2 was 100-times more potent. We conclude that adrenic acid is metabolized in human endothelial cells to 1 alpha, 1 beta-dihomoprostaglandins and can compete with endogenous arachidonic acid for conversion by cyclooxygenase. These findings suggest that adrenic acid may reduce the formation of prostaglandin I2 by the blood vessel.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis / Q000494:pharmacology; D004883:Erucic Acids / Q000378:metabolism*; D005227:Fatty Acids / Q000032:analysis; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000032:analysis; D011458:Prostaglandins E / Q000096:biosynthesis; D011461:Prostaglandins F, Synthetic / Q000096:biosynthesis; D013917:Thrombin / Q000494:pharmacology; D014471:Umbilical Veins
D001095:Arachidonic Acids; D003470:Culture Media; D004883:Erucic Acids; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D011453:Prostaglandins; D011458:Prostaglandins E; D011461:Prostaglandins F, Synthetic; C011395:adrenic acid; C024113:1a,1b-dihomoprostaglandin E2; D016718:Arachidonic Acid; C046934:1,1-dihomo-8-ketoprostaglandin F1alpha; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D013917:Thrombin; D015232:Dinoprostone; D007213:Indomethacin