Research Article Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia Mohammad Badran, 1 Bisher Abuyassin, 1 Saeid Golbidi, 1 Najib Ayas, 2,3,4 and Ismail Laher 1 1 Department of Anesthesiology, Pharmacology and Terapeutics, University of British Columbia, Vancouver, BC, Canada 2 Divisions of Critical Care and Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada 3 Sleep Disorders Program, UBC Hospital, Vancouver, BC, Canada 4 Division of Critical Care Medicine, Providence Healthcare, Vancouver, BC, Canada Correspondence should be addressed to Ismail Laher; ilaher@mail.ubc.ca Received 3 August 2016; Accepted 3 October 2016 Academic Editor: Giuseppe Cirillo Copyright © 2016 Mohammad Badran et al. Tis 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 ofen 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-Dock7 m +/+ Lepr db /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 signifcantly 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. 1. Introduction Obstructive sleep apnea (OSA) involves obstruction of the airways for at least 10 seconds (apnea) or sharp decreases in breathing amplitude (hypopnea) during sleep [1]. OSA is an independent risk factor for cardiovascular disease (CVD) [2] and is also associated with other CVD risk factors such as obesity [3, 4], diabetes [5, 6], and hypertension [7]. Te cardiovascular pathology of OSA has been primarily linked to chronic intermittent hypoxia (CIH) and increased sym- pathetic innervation [8]. OSA leads to CVD through several pathological mechanisms if lef untreated [9]; an important mechanism is through vascular endothelial dysfunction char- acterized by impaired nitric oxide (NO) production, which can ultimately lead to atherosclerosis [10]. Numerous clinical and animal studies demonstrate that OSA and CIH lead to endothelial dysfunction [11–14]. Tere is much support for a bidirectional association between OSA and diabetes [5]. Te estimated prevalence of OSA in diabetic patients is approximately 71%, and 15%– 30% of patients with OSA have diabetes [15]. Te risk of developing diabetes is related to the severity of OSA [16]. Diabetes is associated with cardiovascular disease and increased mortality [17, 18], where nearly 70% of people aged 65 or older with diabetes die from heart disease and are 2 to 4 times more likely to sufer from heart disease and stroke [17]. Endothelial dysfunction is a hallmark of diabetes, with oxidative stress and infammation having important roles in the process [1]. We hypothesized that CIH further exacerbates endothelial dysfunction of diabetic mice. Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 2354870, 9 pages http://dx.doi.org/10.1155/2016/2354870