Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging
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Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. / Oelze, Matthias; Kröller-Schön, Swenja; Steven, Sebastian; Lubos, Edith; Doppler, Christopher; Hausding, Michael; Tobias, Silke; Brochhausen, Christoph; Li, Huige; Torzewski, Michael; Wenzel, Philip; Bachschmid, Markus; Lackner, Karl J; Schulz, Eberhard; Münzel, Thomas; Daiber, Andreas.
in: HYPERTENSION, Jahrgang 63, Nr. 2, 02.2014, S. 390-396.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging
AU - Oelze, Matthias
AU - Kröller-Schön, Swenja
AU - Steven, Sebastian
AU - Lubos, Edith
AU - Doppler, Christopher
AU - Hausding, Michael
AU - Tobias, Silke
AU - Brochhausen, Christoph
AU - Li, Huige
AU - Torzewski, Michael
AU - Wenzel, Philip
AU - Bachschmid, Markus
AU - Lackner, Karl J
AU - Schulz, Eberhard
AU - Münzel, Thomas
AU - Daiber, Andreas
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Aged
KW - Aging/metabolism
KW - Animals
KW - Cells, Cultured
KW - Endothelial Cells/cytology
KW - Endothelium, Vascular/metabolism
KW - Glutathione Peroxidase/deficiency
KW - Humans
KW - Leukocytes/cytology
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Nitric Oxide Synthase Type III/metabolism
KW - Oxidants/metabolism
KW - Oxidative Stress/physiology
KW - Phosphorylation/physiology
U2 - 10.1161/HYPERTENSIONAHA.113.01602
DO - 10.1161/HYPERTENSIONAHA.113.01602
M3 - SCORING: Journal article
C2 - 24296279
VL - 63
SP - 390
EP - 396
JO - HYPERTENSION
JF - HYPERTENSION
SN - 0194-911X
IS - 2
ER -