Abstract
Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor yet identified. This peptide plays an important role in the regulation of arterial tone, in part through its interaction with endogenous vasodilator compounds. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs), we determined the effects of prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 on ET-1 synthesis and secretion from cultured bovine aortic endothelial cells and on ET-1 action in aortic smooth muscle cells. Both PGE2 and PGI2 (vasodilator prostaglandins) caused an approximately 40% inhibition of basal ET-1 secretion and a 50% inhibition of serum-stimulated ET-1 secretion in a dose-related and time course fashion. In contrast, the vasoconstrictor prostaglandin, thromboxane A2, had no effect on ET-1 secretion. PGE2 and PGI2 similarly inhibited the basal production of new ET-1 protein (translation) by 40-50% and inhibited the basal steady-state mRNA expression of ET-1 in bovine aortic endothelial cells by 60-70%. Both prostaglandins also caused an approximately 55% inhibition of ET-1 transcription, as shown by chloramphenicol acetyltransferase reporter studies. PGE2 and PGI2 strongly stimulated cGMP generation; both the PG stimulation of cGMP and the inhibition of ET-1 secretion and translation were reversed by LY83583, a general inhibitor of cGMP generation. The PG-induced inhibition of ET-1 secretion and translation was also reversed by KT5823, an inhibitor of cGMP-dependent protein kinase, but not by (Rp)-adenosine cyclic 3':5'-monophosphate, an inhibitor of protein kinase A activation. PGE2 and PGI2 also inhibited both basal and ET-1-stimulated DNA synthesis in aortic smooth muscle cells by approximately 45% through a cGMP-dependent mechanism. Therefore, two endogenous PGs, known to be important vasodilators in vivo, significantly inhibit the transcription, translation, secretion, and action of ET-1. We propose that the vasodilator action of the PGs results, in part, from their ability to inhibit the production of this potent vasoconstrictor.
Highlights
Endothelin-1(ET-1)is the most potent endogenous va- tide hormones andprostaglandinsT. hese factors interact soconstrictor yet identified
For studies of aortic smooth musclecells,the preparation and plating sults were divided by the normalized -143CAT values, and the of cells were similar, except that fetal bovine aortas were used, and quotient was expressed as CAT activity relative to-143CAT.Experiments were carried out four separate times, each collagenase-containingmedium, followed by rinsing and additional ex- condition usually in duplicate, and all data were combined for graphic posure to collagenase for 2 h to obtain smooth muscle cells [19]
To determine thepossible role of cGMP in theeffects of the data suggest that the PGs inhibit the secretion of ET-1 from prostaglandins, we first determined whether PGE, and PGI, bovine aortic endothelial cells (BAEC), at least in part, by coupling to cGMP formation and can stimulate cGMP generation in culturedBAEC
Summary
Vol 269, No 16, Issue ofApril 22, pp, 11938-11944, 1994 Printed in U.S.A. Prostaglandin E, and Prostacyclin Inhibit the Production and Secretion of Endothelin from Cultured Endothelial Cells*. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs),we determined the effects of prostaglandin E, (PGE,), prostacyclin (PGI,), and thromboxane A, on ET-1 synthesis and secretion from cultured bovine aortic endothelial cells and on ET-1 action in aortic smooth muscle cells. Both PGE, and PGI, (vasodilator prostaglandins) caused an “40% inhibition of basal ET-1secretion and a 50% inhibition of serum-stimulated ET-1 secretion in a dose-retual regulation of vascular factor production and action. Shocked for 1min with 15% glycerol.The cells were washed and incubated for 24 h, and some of the cells that were transfected with
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