Submitted on April 4, 2008
Revised on July 30, 2008
Accepted on August 7, 2008
Intermittent Hypoxia has Organ-Specific Effects on Oxidative Stress
Jonathan C Jun1*, Vladimir Savransky1, Ashika Nanayakkara, Shannon Bevans, Jianguo Li1, Philip L Smith, and Vsevolod Y Polotsky1
1 Johns Hopkins University
* To whom correspondence should be addressed. E-mail: jjun2{at}jhmi.edu.
Obstructive sleep apnea (OSA) is characterized by upper airway collapse, leading to intermittent hypoxia (IH). It has been postulated that IH-induced oxidative stress may be a contributing factor to several chronic diseases associated with OSA. We hypothesize that IH induces systemic oxidative stress by up-regulating NADPH oxidase, a superoxide-generating enzyme. NADPH oxidase is regulated by a cytosolic p47phox subunit, which becomes phosphorylated during enzyme activation. Male C57BL/6J mice were exposed to IH with a FiO2 nadir 5% 60 times/hr during the 12 hr light phase (9am-9pm) for one or four weeks. In the aorta and heart, IH did not affect levels of lipid peroxidation (malondialdehyde, MDA), nitrotyrosine, or p47phox expression and phosphorylation. In contrast, in the liver, exposure to IH for 1 week resulted in a trend to an increase in MDA levels, whereas IH for 4 wks resulted in a 38% increase in MDA levels accompanied by up-regulation of p47phox expression and phosphorylation. Administration of an NADPH oxidase inhibitor, apocynin during IH exposure attenuated IH-induced increases in hepatic MDA. In p47phox 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.
