Arachidonic acid induces endothelin-1 gene expression in vascular endothelial cells

Endothelin-l (ET-1) is a potent vasoconstrictor peptide synthesized and sec reted by vascular endothelial cells. Regulation of ET-1 production occurs a t the level of gene transcription. We previously demonstrated a role for ar achidonic acid as an intracellular mediator in the regulation of gene expre ssion. This study investigated the role of arachidonic acid in induction of ET-1 production in endothelial cells. Challenge of bovine aortic endotheli al cells (BAECs) with arachidonic acid induced a dose- and time-dependent i ncrease in the amount of immunoreactive ET-1 in the supernatant. The maximu m effect was observed at concentrations of 20 mu M. Release of ET-1 by arac hidonic 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 polyunsaturate d fatty acids, whereas saturated fatty acids had no effect. Moreover, inhib itors of the lipoxygenase pathway blocked arachidonic acid-induced release of ET-1. These results suggest that arachidonic acid stimulated the product ion of ET-1 in BAECs by inducing ET-1 gene transcription. Arachidonic acid- induced production of ET-1 is dependent on lipoxygenase products of arachid onate metabolism. (C) 1999 Wiley-Liss, Inc.