Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia.

Mohammad Badran,Najib Ayas,Saeid Golbidi,Ismail Laher,Bisher Abuyassin

doi:10.1155/2016/2354870

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-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 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.

Highlights

Obstructive sleep apnea (OSA) involves obstruction of the airways for at least 10 seconds or sharp decreases in breathing amplitude during sleep [1]
OSA leads to cardiovascular disease (CVD) through several pathological mechanisms if left untreated [9]; an important mechanism is through vascular endothelial dysfunction characterized by impaired nitric oxide (NO) production, which can lead to atherosclerosis [10]
We demonstrate that chronic intermittent hypoxia (CIH) further exacerbates an already compromised endothelial function in diabetic mice as indicated by the deterioration of ACh-dependent vasodilation and basal NO in diabetic mice exposed to CIH

Summary

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]. The cardiovascular pathology of OSA has been primarily linked to chronic intermittent hypoxia (CIH) and increased sympathetic innervation [8]. OSA leads to CVD through several pathological mechanisms if left untreated [9]; an important mechanism is through vascular endothelial dysfunction characterized by impaired nitric oxide (NO) production, which can lead to atherosclerosis [10]. Numerous clinical and animal studies demonstrate that OSA and CIH lead to endothelial dysfunction [11,12,13,14]. 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 suffer from heart disease and stroke [17]. We hypothesized that CIH further exacerbates endothelial dysfunction of diabetic mice

Methods

Results

Conclusion