Intermittent hypoxia has organ-specific effects on oxidative stress

Abstract

Obstructive sleep apnea is characterized by upper airway collapse, leading to intermittent hypoxia (IH). It has been postulated that IH-induced oxidative stress may contribute to several chronic diseases associated with obstructive sleep apnea. We hypothesize that IH induces systemic oxidative stress by upregulating NADPH oxidase, a superoxide-generating enzyme. NADPH oxidase is regulated by a cytosolic p47(phox) subunit, which becomes phosphorylated during enzyme activation. Male C57BL/6J mice were exposed to IH with an inspired O(2) fraction nadir of 5% 60 times/h during the 12-h light phase (9 AM-9 PM) for 1 or 4 wk. In the aorta and heart, IH did not affect lipid peroxidation [malondialdehyde (MDA) level], nitrotyrosine level, or p47(phox) expression and phosphorylation. In contrast, in the liver, exposure to IH for 1 wk resulted in a trend to an increase in MDA levels, whereas IH for 4 wk resulted in a 38% increase in MDA levels accompanied by upregulation of p47(phox) expression and phosphorylation. Administration of an NADPH oxidase inhibitor, apocynin, during IH exposure attenuated IH-induced increases in hepatic MDA. In p47(phox)-deficient mice, MDA levels were higher at baseline and, unexpectedly, decreased during IH. In conclusion, oxidative stress levels and pathways under IH conditions are organ and duration specific.

Sleep Apnea Research in Animals. Past, Present, and Future

“…Furthermore, genetic interventions have been applied to rodents that can yield novel mechanistic insights. Experiments using knockout mice have demonstrated pathologic interactions between IH and nicotinamide adenine dinucleotide reduced oxidase (40), adipose angiopoietin-like 4 (41), and hypoxia-inducible factor-1a (42,43) in mediating downstream consequences of IH.…”

Oxidative Stress in the Carotid Body: Implications for the Cardioventilatory Alterations Induced by Obstructive Sleep Apnea

“…Endothelial dysfunction has been related to the progression of hypertension in OSA patients and animals exposed to intermittent hypoxia due to the increased plasmatic levels of proinflammatory cytokines (Biltagi et al, 2008, Jelic et al, 2008, Jun et al, 2008, Tam et al, 2007, Williams & Scharf, 2007. It is likely that an increased production of ROS induced by the hypoxia-reoxygention cycles may evoke the expression of genes and the synthesis of proinflammatory cytokines, mediated by the activation of transcription factors such as the nuclear factor kappa B (NF-κB), the activator protein 1 and HIF-1 (Semenza & Prahbakar, 2007).…”

Liver enzymes in obstructive sleep apnoea syndrome

“…Possible explanations could be that though serum ALT and AST are considered as desirable non-invasive biomarkers of NAFLD, they are neither sensitive nor specific to diagnose NAFLD and characterize its severity. [34] Also, Jun et al [35] demonstrated that lipid peroxidation is increased in the liver due to CIH in animal modal of OSA, but serum aminotransferases remained within the normal range suggesting the possibility that histopathological changes in the liver are not always associated with a concomitant increase in biochemical markers. Moreover the NASH clinical research network currently recommends serum ferritin to identify NAFLD patients at risk for NASH than serum aminotransferases.…”