on June 8, 2006
Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231511.26860.50
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Submitted on December 9, 2004
Accepted on May 19, 2006
NADPH Oxidase Accounts for Enhanced Superoxide Production and Impaired Endothelium-Dependent Smooth Muscle Relaxation in BK
1-/- Mice
Matthias Oelze ;
From II. Medizinische Klinik (M.O., A.W., P.W., A.L.K., M.C., U.H., A.D., T.M.), Johannes Gutenberg-Universität, Mainz, Germany; Institut für Vegetative Physiologie und Pathophysiologie (J.F., H.E.), Universitätsklinikum Eppendorf, Hamburg, Germany; Institut für Neurale Signalverarbeitung (O.P.), ZMNH, Universität Hamburg, Hamburg, Germany; Vascular Signalling Group (I.F.), Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; Klinik für Innere Medizin II (S.W.), Universitätsklinikum Bonn, Bonn, Germany; Medizinische Klinik III (T.M.), Kardiologie und Angiologie, Universitätsklinikum Eppendorf, Hamburg, Germany.
* To whom correspondence should be addressed. E-mail: tmuenzel{at}uni-mainz.de.
Objective--Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca2+-activated K+ channels (BK). A regulatory BK
1 subunit confers Ca2+, voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the 1-subunit.
Methods and Results--Vascular superoxide in BK1-/- was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity and expression of the cyclic GMP-dependent kinase I (cGK-I) were assessed by Western blotting technique. eNOS, sGC, cGK-I expression and acetylcholine-induced NO production were unaltered in Bk1-/- animals, whereas endothelial function was impaired and the activity of the cGK-I was reduced. Vascular O2- and expression of the NADPH oxidase subunits p67phox and Nox1 were increased. Endothelial dysfunction was normalized by the NADPH oxidase inhibitor apocynin. Potassium chloride- and iberiotoxin-induced depolarization mimicked the effect of BK1-deletion by increasing vascular O2- in an NADPH-dependent fashion.
Conclusions--The deletion of BK1 causes endothelial dysfunction by increasing O2- formation via increasing activity and expression of the vascular NADPH oxidase.
Key words: arterial tone • BKCa channel subunit
1 •
NADPH oxidase •
NO/cGMP pathway •
vascular dysfunction
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