Arachidonic acid induces endothelin-1 gene expression in vascular endothelial cells.
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide synthesized and secreted by vascular endothelial cells. Regulation of ET-1 production occurs at the level of gene transcription. We previously demonstrated a role for arachidonic acid as an intracellular mediator in the regulation of gene expression. This study investigated the role of arachidonic acid in induction of ET-1 production in endothelial cells. Challenge of bovine aortic endothelial cells (BAECs) with arachidonic acid induced a dose- and time-dependent increase in the amount of immunoreactive ET-1 in the supernatant. The maximum effect was observed at concentrations of 20 microM. Release of ET-1 by arachidonic acid was preceded by induction of ET-1 gene expression. Arachidonic acid increased ET-1 gene expression by increasing transcription of the ET-1 gene. The effect of arachidonic acid was mimicked by other polyunsaturated fatty acids, whereas saturated fatty acids had no effect. Moreover, inhibitors of the lipoxygenase pathway blocked arachidonic acid-induced release of ET-1. These results suggest that arachidonic acid stimulated the production of ET-1 in BAECs by inducing ET-1 gene transcription. Arachidonic acid-induced production of ET-1 is dependent on lipoxygenase products of arachidonate metabolism.
Rizzo
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Signal Transduction Laboratory, Methodist Research Institute, Indianapolis, Indiana 46202, USA. mrizzo@clarian.com
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D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012680:Sensitivity and Specificity; D013997:Time Factors
D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D005227:Fatty Acids; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D016718:Arachidonic Acid; D007770:L-Lactate Dehydrogenase