Low-density lipoprotein inhibits receptor-mediated prostaglandin synthesis without affecting calcium and arachidonic acid mobilization in human endothelial cells.
Vascular serotonin 5-HT1 receptors have quiescent constrictor activity that is activated by other vasoactive agents such as histamine. Previously, we observed that the 5-HT1-selective agonist 5-carboxamidotryptamine (5-CT) potentiated histamine-stimulated arachidonic acid (AA) mobilization and prostaglandin production in human aortic endothelial cells (HAEC). In the present study, 5-CT was found to potentiate histamine-stimulated calcium mobilization but had no effect on intracellular calcium when added alone. Treatment of HAEC with human low-density lipoprotein (LDL) for 20 hours inhibited the histamine- plus 5-CT-stimulated production of prostaglandin F2alpha (PGF2alpha) and the prostacyclin metabolite 6-keto-PGF1alpha. However, the effects of histamine and histamine potentiation by 5-CT on intracellular Ca mobilization and AA release were resistant to LDL treatment. Conversely, the subsequent receptor-independent conversion of AA to prostaglandins was inhibited by LDL. These results demonstrate that histamine and serotonin receptor activity, measured as the stimulation of Ca and AA mobilization, is resistant to LDL exposure under mild oxidizing conditions, whereas the receptor-independent synthesis of prostaglandins is inhibited by LDL. The results also suggest that the LDL-stimulated mobilization of cellular AA is responsible for the LDL-mediated inhibition of prostaglandin synthesis. These findings suggest a mechanism by which LDL and/or atherosclerosis could promote the vascular liberation of AA that is not converted to endothelium-derived prostaglandins and is therefore available as substrate for the production of other eicosanoids.
Kilbourne
Edward J
EJ
Endocrinology and Reproductive Disorders Division, Women's Health Research Institute, Wyeth Research, Collegeville, Pennsylvania, USA. Kilboue@wyeth.com
D015121:6-Ketoprostaglandin F1 alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001011:Aorta / Q000473:pathology; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D015237:Dinoprost / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006632:Histamine / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D044263:Receptors, Serotonin, 5-HT1 / Q000502:physiology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D003470:Culture Media; D008077:Lipoproteins, LDL; D044263:Receptors, Serotonin, 5-HT1; C099252:oxidized low density lipoprotein; D016718:Arachidonic Acid; D012701:Serotonin; D015121:6-Ketoprostaglandin F1 alpha; D006632:Histamine; C047087:5-carboxamidotryptamine; D015237:Dinoprost; D000242:Cyclic AMP; D002118:Calcium