Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling
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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. / Mollnau, Hanke; Wendt, Maria; Szöcs, Katalin; Lassègue, Bernard; Schulz, Eberhard; Oelze, Mathias; Li, Huige; Bodenschatz, Martin; August, Michael; Kleschyov, Andrei L; Tsilimingas, Nikolaus; Walter, Ulrich; Förstermann, Ulrich; Meinertz, Thomas; Griendling, Kathy; Münzel, Thomas.
in: CIRC RES, Jahrgang 90, Nr. 4, 08.03.2002, S. 58-65.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling
AU - Mollnau, Hanke
AU - Wendt, Maria
AU - Szöcs, Katalin
AU - Lassègue, Bernard
AU - Schulz, Eberhard
AU - Oelze, Mathias
AU - Li, Huige
AU - Bodenschatz, Martin
AU - August, Michael
AU - Kleschyov, Andrei L
AU - Tsilimingas, Nikolaus
AU - Walter, Ulrich
AU - Förstermann, Ulrich
AU - Meinertz, Thomas
AU - Griendling, Kathy
AU - Münzel, Thomas
PY - 2002/3/8
Y1 - 2002/3/8
N2 - 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 gp91(phox) 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 p22(phox), nox1, nox4, and gp91(phox) 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), gp91(phox) (3-fold), p22(phox) (3-fold), NOS III mRNA, and protein. NOS-inhibition with N(G)-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.
AB - 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 gp91(phox) 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 p22(phox), nox1, nox4, and gp91(phox) 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), gp91(phox) (3-fold), p22(phox) (3-fold), NOS III mRNA, and protein. NOS-inhibition with N(G)-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.
KW - Angiotensin II/administration & dosage
KW - Animals
KW - Aorta/metabolism
KW - Blood Pressure/drug effects
KW - Cell Adhesion Molecules/metabolism
KW - Cyclic GMP/metabolism
KW - Cyclic GMP-Dependent Protein Kinase Type I
KW - Cyclic GMP-Dependent Protein Kinases/metabolism
KW - Disease Models, Animal
KW - Enzyme Activation/drug effects
KW - Guanylate Cyclase
KW - In Vitro Techniques
KW - Infusions, Parenteral
KW - Membrane Glycoproteins/genetics
KW - Membrane Transport Proteins
KW - Microfilament Proteins
KW - NAD/pharmacology
KW - NADH, NADPH Oxidoreductases/genetics
KW - NADP/pharmacology
KW - NADPH Dehydrogenase/genetics
KW - NADPH Oxidase 1
KW - NADPH Oxidase 2
KW - NADPH Oxidase 4
KW - NADPH Oxidases/genetics
KW - Nitric Oxide/metabolism
KW - Nitric Oxide Synthase/genetics
KW - Nitric Oxide Synthase Type III
KW - Phosphoproteins/genetics
KW - Protein Kinase C/metabolism
KW - Rats
KW - Rats, Wistar
KW - Receptors, Cytoplasmic and Nuclear/metabolism
KW - Signal Transduction/drug effects
KW - Soluble Guanylyl Cyclase
KW - Superoxides/metabolism
KW - Vasodilation/drug effects
KW - Vasodilator Agents/pharmacology
U2 - 10.1161/01.res.0000012569.55432.02
DO - 10.1161/01.res.0000012569.55432.02
M3 - SCORING: Journal article
C2 - 11884382
VL - 90
SP - 58
EP - 65
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 4
ER -