title: Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia.
abstract: Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH.Methods. Adult male diabetic (BKS.Cg-Dock7m+/+Leprdb/J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining.Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group.Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mohammad
authors.identifier: 0000-0001-7073-741X
authors.initials: M
authors.lastname: Badran
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Bisher
authors.identifier: 0000-0003-3923-6646
authors.initials: B
authors.lastname: Abuyassin
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Saeid
authors.identifier: 0000-0001-9166-2023
authors.initials: S
authors.lastname: Golbidi
authors.affiliation: Divisions of Critical Care and Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Sleep Disorders Program, UBC Hospital, Vancouver, BC, Canada; Division of Critical Care Medicine, Providence Healthcare, Vancouver, BC, Canada.
authors.forename: Najib
authors.initials: N
authors.lastname: Ayas
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ismail
authors.identifier: 0000-0002-3917-4417
authors.initials: I
authors.lastname: Laher
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D000860:Hypoxia / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive / Q000201:enzymology / Q000378:metabolism
chemical_list: D019001:Nitric Oxide Synthase