This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/8/1753    most recent 01.ATV.0000231511.26860.50v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oelze, M. Articles by Münzel, T. Search for Related Content PubMed PubMed Citation Articles by Oelze, M. Articles by Münzel, T.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1753.)
© 2006 American Heart Association, Inc.

Vascular Biology

NADPH Oxidase Accounts for Enhanced Superoxide Production and Impaired Endothelium-Dependent Smooth Muscle Relaxation in BKß1^–/– Mice

Matthias Oelze; Ascan Warnholtz; Jörg Faulhaber; Philip Wenzel; Andrei L. Kleschyov; Meike Coldewey; Ulrich Hink; Olaf Pongs; Ingrid Fleming; Sven Wassmann; Thomas Meinertz; Heimo Ehmke; Andreas Daiber; Thomas Münzel

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.

Correspondence to Thomas Münzel, II.Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, D-55131 Mainz, Germany. 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 BKß1 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 ß1-subunit.

Methods and Results— Vascular superoxide in BKß1^–/– 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 Bkß1^–/– animals, whereas endothelial function was impaired and the activity of the cGK-I was reduced. Vascular O₂^– and expression of the NADPH oxidase subunits p67^phox and Nox1 were increased. Endothelial dysfunction was normalized by the NADPH oxidase inhibitor apocynin. Potassium chloride- and iberiotoxin-induced depolarization mimicked the effect of BKß1-deletion by increasing vascular O₂^– in an NADPH-dependent fashion.

Conclusions— The deletion of BKß1 causes endothelial dysfunction by increasing O₂^– formation via increasing activity and expression of the vascular NADPH oxidase.

Endothelium-dependent relaxation is compromised in mice lacking the ß1 subunit of the large conductance, Ca²⁺-activated K⁺ channel. Expression of the NADPH oxidase subunit p67^phox and aortic superoxide are increased, but endothelial NO production is normal. Thus, BKß1 deletion induces endothelial dysfunction, at least in part, via NADPH oxidase-mediated ROS production.

Key Words: arterial tone • BK_Ca channel subunit ß1 • NADPH oxidase • NO/cGMP pathway • vascular dysfunction

This article has been cited by other articles:

				F. Violi, V. Sanguigni, R. Carnevale, A. Plebani, P. Rossi, A. Finocchi, C. Pignata, D. De Mattia, B. Martire, M. C. Pietrogrande, et al. Hereditary Deficiency of gp91phox Is Associated With Enhanced Arterial Dilatation: Results of a Multicenter Study Circulation, October 20, 2009; 120(16): 1616 - 1622. [Abstract] [Full Text] [PDF]

				P. Wenzel, S. Schuhmacher, J. Kienhofer, J. Muller, M. Hortmann, M. Oelze, E. Schulz, N. Treiber, T. Kawamoto, K. Scharffetter-Kochanek, et al. Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction Cardiovasc Res, November 1, 2008; 80(2): 280 - 289. [Abstract] [Full Text] [PDF]

				A. Jabs, S. Gobel, P. Wenzel, A. L. Kleschyov, M. Hortmann, M. Oelze, A. Daiber, and T. Munzel Sirolimus-induced vascular dysfunction increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2130 - 2138. [Abstract] [Full Text] [PDF]

				A. Just, C. L. Whitten, and W. J. Arendshorst Reactive oxygen species participate in acute renal vasoconstrictor responses induced by ETA and ETB receptors Am J Physiol Renal Physiol, April 1, 2008; 294(4): F719 - F728. [Abstract] [Full Text] [PDF]

				A. Just, A. J. M. Olson, C. L. Whitten, and W. J. Arendshorst Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H83 - H92. [Abstract] [Full Text] [PDF]