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Endothelin-1 Induces NAD(P)H Oxidase in Human Endothelial Cells

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Abstract

Superoxide anions (O•−2) induce oxidative stress and reduce endothelial NO availability by peroxynitrite formation. In human endothelial cells gp91phox was identified as the limiting subunit of the forming NAD(P)H oxidase. Because endothelin-1 (ET-1) is considered as a pro-atherosclerotic stimulus, we analyzed the effect of ET-1 on gp91phox expression and O•−2 generation in primary cultures of human umbilical vein endothelial cells (HUVECs). The gp91phox mRNA expression was quantified by standard calibrated competitive reverse transcriptase–polymerase chain reaction. ET-1 induces gp91phox mRNA expression in HUVEC (max. after 1 h). The induction of gp91phox expression was dose-dependent, reaching its maximum at 10 nmol/L ET-1. The increased gp91phox expression is mediated by endothelial receptor type B (ETB). Furthermore, ET-1 augments O•−2 generation in human endothelial cells as measured by coelenterazine chemiluminescence. These data support a new mechanism: how ET-1 increases oxidative stress in the vessel wall leading to endothelial dysfunction and enhanced susceptibility to atherosclerosis.

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    Abbreviations used: CL, chemiluminescence; ET-1, endothelin-1; ETB, endothelin receptor type B; HUVECs, human umbilical vein endothelial cells; RT-PCR, reverse transcriptase–polymerase chain reaction; SOD, superoxide dismutase

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