Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea

dc.creatorMabry, Steveen_US
dc.creatorBradshaw, Jessicaen_US
dc.creatorGardner, Jenniferen_US
dc.creatorWilson, Elizabethen_US
dc.creatorCunningham, Rebeccaen_US
dc.creator.orcid0000-0003-0719-8059 (Mabry, Steve)
dc.descriptionResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Pharmacology & Neuroscience Award - 1st Placeen_US
dc.description.abstractBackground: Obstructive sleep apnea (OSA) is a highly prevalent sleeping disorder in the USA with known sex differences in prevalence and severity. Men have a higher incidence and experience greater severity of OSA than women. However, recent reports indicate the incidence of OSA in women, particularly mild cases of OSA, may be under-reported and left untreated. OSA is characterized by elevated oxidative stress and inflammation, mechanisms that involve mitochondrial function. This study addressed the role of 1) sex and 2) mitochondrial oxidative stress in OSA induced circulatory oxidative stress and inflammatory cytokines. Methods: Adult Sprague-Dawley male and female rats were implanted (s.c.) with an osmotic pump containing either MitoTEMPOL (mitochondrial oxidative stress inhibitor; MT) or saline vehicle and then exposed to a model of OSA, chronic intermittent hypoxia (CIH), or normoxic room-air for 14 days. The CIH protocol consisted of 10 CIH cycles/hour/8 hrs/day, in which each CIH cycle was composed of 3 minutes of normoxia at 21% O2 and 3 minutes of hypoxia at 10% O2. This protocol replicates an apnea-hypopnea index (AHI) of 10, which is consistent with mild OSA in humans. At the conclusion of the CIH protocol, rats were sacrificed and plasma was collected to quantify markers of oxidative stress (Advanced Oxidized Protein Products, AOPP) and inflammation (pro-inflammatory IL-6, anti-inflammatory IL-10, IL-6/IL-10 ratio). To determine statistical significance, ANOVA followed by Tukey’s post-hoc test was used. Significance level was set a p<0.05. Results: We found circulating oxidative stress was dependent on CIH and sex. Sex differences were observed in control normoxic rats, in which females had higher oxidative stress than males. Interestingly, the impact of CIH on oxidative stress was dependent on sex, wherein CIH decreased oxidative stress in females but increased oxidative stress in males. Inhibiting mitochondria-associated oxidative stress reduced oxidative stress in vehicle females, but only blocked the effect of CIH-induced oxidative stress in males. In contrast to oxidative stress, CIH increased the level of IL-6 only in females. Further, CIH overall induced a pro-inflammatory state as measured by an elevated IL6/IL10 ratio in females. The inflammatory effects of CIH in females were blocked by inhibiting mitochondrial-associated oxidative stress, despite no effect on circulating oxidative stress in CIH. Neither CIH nor MT impacted inflammatory markers in males. Discussion: These results indicate CIH-induced mechanisms underlying oxidative stress and inflammation are dependent on sex. Specifically, males experience a mitochondria-associated oxidative stress phenotype and females experience a mitochondria-associated inflammatory phenotype. These findings indicate that the OSA phenotype is sex-dependent, which may be related to the under-reported OSA incidence in women compared to men. Further, these data indicate that women may be at unique risk from OSA, particularly when AHIs are mild. Interestingly, inhibition of mitochondrial oxidative stress may be a potential drug target for both men and women with OSA.en_US
dc.description.sponsorshipNIH R01 NS0091359; AHA 22PRE-900431; AHA 22POST-903250; NIH T32 AG020494en_US
dc.titleSex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apneaen_US