title: Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging.
abstract: Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1-deficient (GPx-1(-/-)) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1(-/-) mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1(-/-) -mice as compared with age-matched controls. Oxidant formation, detected by 3-nitrotyrosine staining and dihydroethidine-based fluorescence microtopography, was increased in the aged GPx-1(-/-) mice. Aging per se caused a substantial protein kinase C- and protein tyrosine kinase-dependent phosphorylation as well as S-glutathionylation of endothelial NO synthase associated with uncoupling, a phenomenon that was more pronounced in aged GPx-1(-/-) mice. GPx-1 ablation increased adhesion of leukocytes to cultured endothelial cells and CD68 and F4/80 staining in cardiac tissue. Aged GPx-1(-/-) mice displayed increased oxidant formation as compared with their wild-type littermates, triggering redox-signaling pathways associated with endothelial NO synthase dysfunction and uncoupling. Thus, our data demonstrate that aging leads to decreased NO bioavailability because of endothelial NO synthase dysfunction and uncoupling of the enzyme leading to endothelial dysfunction, vascular remodeling, and promotion of adhesion and infiltration of leukocytes into cardiovascular tissue, all of which was more prominent in aged GPx-1(-/-) mice.
authors.affiliation: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, II. Medizinische Klinik, Langenbeckstr. 1, 55131 Mainz, Germany. : andreas.daiber@bioredox.com.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.forename: Edith
authors.initials: E
authors.lastname: Lubos
authors.forename: Christopher
authors.initials: C
authors.lastname: Doppler
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Silke
authors.initials: S
authors.lastname: Tobias
authors.forename: Christoph
authors.initials: C
authors.lastname: Brochhausen
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Markus
authors.initials: M
authors.lastname: Bachschmid
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D000094765:Glutathione Peroxidase GPX1
chemical_list: D016877:Oxidants; D005979:Glutathione Peroxidase; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000094765:Glutathione Peroxidase GPX1
keywords: aging; oxidative stress; vascular function