Novel proteins associated with chronic intermittent hypoxia and obstructive sleep apnea: From rat model to clinical evidence.

Xiaojun Tang,Ying Zhang,Mengmeng Li,Kang Jiang,Shisheng Li,Qinglai Tang,Lu Guo,Peiying Huang,Shiying Zeng,Xinming Yang

doi:10.1371/journal.pone.0253943

Xiaojun Tang, Ying Zhang + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0253943

Copy DOI

Abstract

ObjectiveTo screen for obstructive sleep apnea (OSA) biomarkers, isobaric tags for relative and absolute quantitation (iTRAQ)-labeled quantitative proteomics assay was used to identify differentially expressed proteins (DEPs) during chronic intermittent hypoxia (CIH).MethodThe iTRAQ technique was applied to compare DEPs in the serum of a CIH rat model and control group. Biological analysis of DEPs was performed using Gene Ontology and Kyoto Encyclopedia to explore related biological functions and signaling pathways. Enzyme-linked immunosorbent assay (ELISA) was performed to validate their expression in sera from patients with OSA and CIH rats.ResultsTwenty-three DEPs (fold change ≥1.2 or ≤0.833, p<0.05) were identified, and two DEPs (unique peptides>3 and higher coverage) were further verified by ELISA in the CIH rat model and OSA subject: apolipoprotein A-IV (APOA4, p<0.05) and Tubulin alpha-1A chain (TUBA1A, p<0.05). Both groups showed significant differences in the expression levels of DEPs between the CIH and control groups and the severe OSA and non-OSA groups. APOA4 was found to be upregulated and TUBA1A downregulated in both the sera from OSA patients and CIH rats, on comparing proteomics results with clinical results. There were two pathways that involved three DEPs, the mitogen-activated protein kinase (MAPK) signaling pathway (p<0.05) and cytokine-cytokine receptor interaction (p<0.05).ConclusionAPOA4 and TUBA1A may be potential novel biomarkers for CIH and OSA, and may play an important role in the development of OSA complications.

Highlights

APOA4 was found to be upregulated and tubulin alpha-1A chain (TUBA1A) downregulated in both the sera from Obstructive sleep apnea (OSA) patients and chronic intermittent hypoxia (CIH) rats, on comparing proteomics results with clinical results
Obstructive sleep apnea (OSA), a common respiratory disorder characterized by recurring conditions of complete or partial collapse of the upper airway during sleep, is an independent risk factor for many clinical complications [1], such as cardiovascular and olfactory pulmonary comorbidities, the severity of which is greater in the elderly [2,3]
Cardiovascular risk in patients with OSA is reduced after nonresectable pharyngoplasty because apnea or hypopnea improves after treatment [5]

Summary

Introduction

Obstructive sleep apnea (OSA), a common respiratory disorder characterized by recurring conditions of complete or partial collapse of the upper airway during sleep, is an independent risk factor for many clinical complications [1], such as cardiovascular and olfactory pulmonary comorbidities, the severity of which is greater in the elderly [2,3]. Apnea or hypopnea results from upper airway obstruction, leading to chronic intermittent hypoxia (CIH), carbon dioxide retention, repeated intrathoracic negative pressure, and abnormal sleep structure, which are linked to oxidative stress, inflammation, and cardiovascular and metabolic diseases. CIH increases the production of reactive oxygen and enhances the level of oxidative stress, promoting sympathetic excitement and blood pressure, contributing to endothelial dysfunction, and predisposing patients to complications, such as cardiovascular disease, metabolic dysfunction, and cognitive decline [6]. The specific contribution of CIH to OSA complications remains unclear

Methods

Results

Conclusion