title: Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II.
abstract: Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6C(high) and CD11b(+)/iNOS(high) leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM(+)) monocytes in ATII-infused LysM(iDTR) transgenic mice prevented eNOS glutathionylation and eNOS-derived N(ω)-nitro-L-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysM(iDTR) mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII-induced endothelial dysfunction. In summary, ATII induces an inflammatory cell-dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM(+) monocytes.
authors.affiliation: From the 2nd Medical Clinic, Center for Thrombosis and Hemostasis, and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.affiliation: Center for Thrombosis and Hemostasis, and.
authors.forename: Hanhan
authors.initials: H
authors.lastname: Hu
authors.affiliation: From the 2nd Medical Clinic, Center for Thrombosis and Hemostasis, and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.affiliation: Center for Thrombosis and Hemostasis, and.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönfelder
authors.affiliation: the Clinic for Cardiology and Angiology, Hannover School of Medicine, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany, and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.affiliation: From the 2nd Medical Clinic.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Mikhed
authors.affiliation: Center for Thrombosis and Hemostasis, and Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Brähler
authors.affiliation: From the 2nd Medical Clinic, Center for Thrombosis and Hemostasis, and.
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.affiliation: Center for Thrombosis and Hemostasis, and the Stanford School of Medicine, Stanford, California 94305.
authors.forename: Moritz
authors.initials: M
authors.lastname: Brandt
authors.affiliation: From the 2nd Medical Clinic.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Karbach
authors.affiliation: Center for Thrombosis and Hemostasis, and Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.affiliation: From the 2nd Medical Clinic.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.affiliation: the Clinic for Cardiology and Angiology, Hannover School of Medicine, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany, and.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: the Clinic for Cardiology and Angiology, Hannover School of Medicine, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany, and.
authors.forename: Julian
authors.initials: J
authors.lastname: Widder
authors.affiliation: From the 2nd Medical Clinic.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: From the 2nd Medical Clinic.
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: From the 2nd Medical Clinic, Center for Thrombosis and Hemostasis, and wenzelp@uni-mainz.de.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000276:immunology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000276:immunology*; D018384:Oxidative Stress
chemical_list: D000804:Angiotensin II; D001708:Biopterins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin
keywords: Angiotensin II; Endothelial Dysfunction; Inflammation; Monocyte; Nitric-oxide Synthase; Tetrahydrobiopterin (BH4)