Published online before print February 7, 2002, doi: 10.1161/01.RES.0000012569.55432.02
© 2002 American Heart Association, Inc.
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Effects of Angiotensin II Infusion on the Expression and Function of NAD(P)H Oxidase and Components of Nitric Oxide/cGMP Signaling
From the Division of Cardiology (H.M., M.W., E.S., M.O., M.B., M.A., A.L.K., T. Meinertz., T. Münzel) and Cardiovascular Surgery (N.T.), University Hospital Eppendorf, Hamburg, Germany; the Department of Clinical Biochemistry and Pathobiochemistry (U.W.), University of Würzburg, Germany; the Department of Pharmacology (H.L., U.F.), Johannes Gutenberg University, Mainz, Germany; and the Department of Cardiology (K.S., B.L., K.G.), Emory University, Atlanta, Ga.
Correspondence to Thomas Münzel, MD, Universitätskrankenhaus Eppendorf, Abteilung für Kardiologie, Martinistraße 52, 20246 Hamburg, Germany. E-mail muenzel{at}uke.uni-hamburg.de
Abstract
Angiotensin II infusion causes endothelial dysfunction by increasing NAD(P)H oxidase-mediated vascular superoxide production. However, it remains to be elucidated how in vivo angiotensin II treatment may alter the expression of the gp91phox isoforms and the endothelial nitric oxide synthase (NOS III) and subsequent signaling events and whether, in addition to the NAD(P)H oxidase, NOS III contributes to vascular superoxide formation. We therefore studied the influence of in vivo angiotensin II treatment (7 days) in rats on endothelial function and on the expression of the NAD(P)H oxidase subunits p22phox, nox1, nox4, and gp91phox and NOS III. Further analysis included the expression of NO-downstream targets, the soluble guanylyl cyclase (sGC), the cGMP-dependent protein kinase I (cGK-I), and the expression and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P-VASP). Angiotensin II caused endothelial dysfunction and increased vascular superoxide. Likewise, we found an increase in vascular protein kinase C (PKC) activity, in the expression of nox1 (6- to 7-fold), gp91phox (3-fold), p22phox (3-fold), NOS III mRNA, and protein. NOS-inhibition with NG-nitro-L-arginine decreased superoxide in vessels from angiotensin II-treated animals, compatible with NOS-uncoupling. Vascular NO assessed with electron paramagnetic resonance was markedly reduced. Likewise, a decrease in sGC-expression and P-VASP levels was found. In vivo PKC-inhibition with chelerythrine reduced angiotensin II-induced superoxide production and markedly inhibited upregulation of NAD(P)H oxidase subunits. We therefore conclude that angiotensin II-induced increases in the activity and the expression of NAD(P)H oxidase are at least in part PKC-dependent. NADPH oxidase-induced superoxide production may trigger NOS III uncoupling, leading to impaired NO/cGMP signaling and to endothelial dysfunction in this animal model. The full text of this article is available at http://www.circresaha.org.
Key Words: angiotensin II • nitric oxide synthase uncoupling • nox expression • cGMP-dependent protein kinase • vasodilator-stimulated phosphoprotein
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