Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter
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Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter. / Kähler, Jan; Mendel, Sabine; Weckmüller, Jörn; Orzechowski, Hans Dieter; Mittmann, Clemens; Köster, Ralf; Paul, Martin; Meinertz, Thomas; Münzel, Thomas.
in: J MOL CELL CARDIOL, Jahrgang 32, Nr. 8, 2000, S. 1429-1437.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter
AU - Kähler, Jan
AU - Mendel, Sabine
AU - Weckmüller, Jörn
AU - Orzechowski, Hans Dieter
AU - Mittmann, Clemens
AU - Köster, Ralf
AU - Paul, Martin
AU - Meinertz, Thomas
AU - Münzel, Thomas
PY - 2000
Y1 - 2000
N2 - Modulation of the biosynthesis of the vasoconstrictor peptide endothelin-1 by oxygen-derived free radicals generated by xanthine oxidase or hydrogen peroxide was studied in cultured endothelial cells. Endothelin-1 metabolism was investigated at the level of endothelin-1 promoter, preproendothelin-1 mRNA and intracellular big endothelin-1. Endothelin-1 mRNA, as characterized by Northern blotting, was increased both time- and dose-dependently by xanthine oxidase to up to 500% above baseline. Analysis of endothelin-1 promoter activity using a construct containing 1329 bp of the endothelin-1 promoter revealed that promoter activity was increased up to eight-fold by incubation with xanthine oxidase. Specificity was ascertained by co-incubation with superoxide dismutase and catalase leading to inhibition of the effect of xanthine oxidase. A significant contribution of nitric oxide was ruled out, since NOS III-mRNA transcription remained unchanged and L-NAME did not significantly alter endothelin-1 promoter activity. Synthesis of intracellular big endothelin-1 protein was increased dose-dependently by xanthine oxidase. Our results indicate that oxidative stress leads to increased endothelial synthesis of big endothelin-1, which is a previously unknown mechanism and may help to understand the detrimental association of increased oxidative stress and elevated endothelin-1 levels in pathophysiological conditions promoting atherosclerosis. (C) 2000 Academic Press.
AB - Modulation of the biosynthesis of the vasoconstrictor peptide endothelin-1 by oxygen-derived free radicals generated by xanthine oxidase or hydrogen peroxide was studied in cultured endothelial cells. Endothelin-1 metabolism was investigated at the level of endothelin-1 promoter, preproendothelin-1 mRNA and intracellular big endothelin-1. Endothelin-1 mRNA, as characterized by Northern blotting, was increased both time- and dose-dependently by xanthine oxidase to up to 500% above baseline. Analysis of endothelin-1 promoter activity using a construct containing 1329 bp of the endothelin-1 promoter revealed that promoter activity was increased up to eight-fold by incubation with xanthine oxidase. Specificity was ascertained by co-incubation with superoxide dismutase and catalase leading to inhibition of the effect of xanthine oxidase. A significant contribution of nitric oxide was ruled out, since NOS III-mRNA transcription remained unchanged and L-NAME did not significantly alter endothelin-1 promoter activity. Synthesis of intracellular big endothelin-1 protein was increased dose-dependently by xanthine oxidase. Our results indicate that oxidative stress leads to increased endothelial synthesis of big endothelin-1, which is a previously unknown mechanism and may help to understand the detrimental association of increased oxidative stress and elevated endothelin-1 levels in pathophysiological conditions promoting atherosclerosis. (C) 2000 Academic Press.
KW - Endothelin-1
KW - Oxygen-derived radicals
KW - Preproendothelin-1 mRNA
KW - Promoter
UR - http://www.scopus.com/inward/record.url?scp=0033858177&partnerID=8YFLogxK
U2 - 10.1006/jmcc.2000.1178
DO - 10.1006/jmcc.2000.1178
M3 - SCORING: Journal article
AN - SCOPUS:0033858177
VL - 32
SP - 1429
EP - 1437
JO - J MOL CELL CARDIOL
JF - J MOL CELL CARDIOL
SN - 0022-2828
IS - 8
ER -