Abstract
The present study investigated the nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response element (ARE) signaling pathway in patients with moderate to severe obstructive sleep apnea-hypopnea syndrome (OSAHS). Their correlation with neurocognitive impairment metrics was investigated to explore potential pathogenesis in OSAHS. Forty-eight patients with OSAHS and 28 controls underwent testing with the Epworth Sleep Scale (ESS), MATRICS Consensus Cognitive Battery (MCCB), Stroop Color and Word Test, polysomnography (PSG), and measurements of the concentration of plasma superoxide dismutase (SOD) and thioredoxin (Trx). Further, 20 pairs of matched patients with OSAHS and controls were selected for measurement of the expression (protein and mRNA) of Nrf2 and of its downstream antioxidase, heme oxygenase-1 (HO-1), in peripheral mononuclear cells (PBMCs). Finally, correlations between neurocognitive impairment and the above metrics were analyzed. Expression of Nrf2 and HO-1 mRNA and protein in the PBMCs, as well as plasma SOD and Trx levels, were significantly reduced in patients with OSAHS. After adjusting for education, sex, age, and smoking index, the expression of Nrf2-ARE signaling pathway proteins (or mRNA) was closely correlated with sleep respiratory parameters. An inverse relationship was demonstrated between the expression of nuclear Nrf2 in PBMCs, concentration of plasma SOD and Trx, and apnea-hypopnea index (AHI) in patients with OSAHS. Trx, nuclear Nrf2 protein, and HO-1 protein were also negatively correlated with the percent of time that SaO2 was less than 90% (TSat90). Total Nrf2 protein level was positively correlated with AHI and TSat90 and negatively correlated with minimum SaO2 (LSaO2), while nuclear Nrf2 protein and HO-1 protein were positively correlated with LSaO2. Moreover, significant positive correlations were found between maze scores and expression of nuclear Nrf2 protein, HO-1 protein, and SOD and Trx levels. Furthermore, inverse relationships between total Nrf2 protein in PBMCs and HVLT-R and maze scores were found. Multiple linear regression showed plasma Trx concentration as a potential predictor of maze and BVMT-R scores. In conclusion, the expression of Nrf2-ARE molecules and related antioxidases is significantly decreased in patients with OSAHS and is correlated with neurocognitive dysfunction. The Nrf2-ARE signaling pathway may play a crucial role in neurocognitive impairment in patients with moderate to severe OSAHS. Further studies are needed to explore the exact mechanisms and potential treatment interventions.
Highlights
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by nocturnal intermittent hypoxia/reoxygenation and sleep disturbances and is caused by repeated upper respiratory tract collapse during sleep
Plasma superoxide dismutase (SOD) and Trx levels as well as Nrf2 and heme oxygenase-1 (HO-1) mRNA and protein expression levels in peripheral blood mononuclear cells (PBMCs) were significantly lower in the SOD 312.7 (248.0–387.8) 78.2 (46.4–224.6) ≤0.001∗∗b
The present study shows that NAB: maze scores are positively correlated with total Nrf2 protein expression, nuclear Nrf2 protein, HO-1 protein in PBMCs, and plasma SOD and Trx levels in patients with OSAHS after adjusting for age, sex, education, and smoking index
Summary
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by nocturnal intermittent hypoxia/reoxygenation and sleep disturbances and is caused by repeated upper respiratory tract collapse during sleep. Many studies have demonstrated that overproduction of oxidative stress products induced by CIH impair neurons and neural signaling pathways, and this likely plays a crucial role in the development of neurocognitive deficits in OSAHS [4]. It has been demonstrated that dysfunction of the Nrf2-ARE signaling pathway plays an important role in the development of cognitive decline in patients with neurodegenerative diseases [6, 7]. The present study sought to evaluate whether there are differences in the expression of Nrf mRNA and its downstream antioxidase, HO-1, in peripheral blood mononuclear cells (PBMCs) and related important antioxidases between patients with moderate to severe OSAHS and healthy controls. We analyzed correlations between the Nrf2-ARE signaling pathway and neurocognitive impairment to explore the possible mechanisms of cognitive impairment seen in patients with OSAHS and to provide a foundation for further investigations. The MATRICS Consensus Cognitive Battery (MCCB) [8] is an internationally
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