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Oxidative Medicine and Cellular Longevity
Volume 2016, Article ID 2354870, 9 pages
Research Article

Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

1Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
2Divisions of Critical Care and Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
3Sleep Disorders Program, UBC Hospital, Vancouver, BC, Canada
4Division of Critical Care Medicine, Providence Healthcare, Vancouver, BC, Canada

Received 3 August 2016; Accepted 3 October 2016

Academic Editor: Giuseppe Cirillo

Copyright © 2016 Mohammad Badran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.