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CARDIOVASCULAR |
1 Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, D-01307 Dresden, Germany
2 Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202-2689, USA
The flowing blood generates shear stress at the endothelial cell surface. In endothelial cells, NAD(P)H oxidase complexes have been identified as major sources of superoxide anion (·O2–) formation. In this study, we analysed the effect of laminar shear stress on ·O2– formation by cytochrome c reduction assay and on NAD(P)H oxidase subunit expression by standard calibrated competitive reverse transcription-polymerase chain reaction and Western blot in human endothelial cells. Primary cultures of human umbilical vein endothelial cells were exposed to laminar shear stress in a cone-and-plate viscometer for up to 24 h. Short-term application of shear stress transiently induced ·O2– formation. This was inhibited by NAD(P)H oxidase inhibitor gp91ds-tat, but NAD(P)H oxidase subunit expression was unchanged. Long-term arterial laminar shear stress (30 dyne cm–2, 24 h) down-regulated ·O2– formation, and mRNA and protein expression of NAD(P)H oxidase subunits Nox2/gp91phox and p47phox. In parallel, endothelial NO formation and eNOS, but not Cu/Zn SOD, protein expression was increased. Down-regulation of ·O2– formation, gp91phox and p47phox expression by long-term laminar shear stress was blocked by L-NAME. NO donor DETA-NO down-regulates ·O2– formation, gp91phox and p47phox expression in static cultures. In conclusion, our data suggest a transient activation of ·O2– formation by short-term shear stress, followed by a down-regulation of endothelial NAD(P)H oxidase in response to long-term laminar shear stress. NO-mediated down-regulation by shear stress preferentially affects the gp91phox/p47phox-containing NAD(P)H oxidase complex. This mechanism might contribute to the regulation of endothelial NO/·O2– balance and the vasoprotective potential of physiological levels of laminar shear stress.
(Received 5 April 2006;
accepted after revision 24 July 2006;
first published online 27 July 2006)
Corresponding author H. Morawietz: University of Technology Dresden, Medical Faculty Carl Gustav Carus, Department of Vascular Endothelium and Microcirculation, Fetscherstr. 74, D-01307 Dresden, Germany. Email: henning.morawietz{at}tu-dresden.de
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