Valentim-Coelho Cristina, Saraiva Joana, Osório Hugo, Antunes Marília, Vaz Fátima, Neves Sofia, Pinto Paula, Bárbara Cristina, Penque Deborah
Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge - INSA, 1649-016 Lisboa, Portugal; Centro de Toxicogenómica e Saúde Humana (ToxOmics), Comprehensive Health Research Center (CHRC), Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal.
Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge - INSA, 1649-016 Lisboa, Portugal; Centro de Toxicogenómica e Saúde Humana (ToxOmics), Comprehensive Health Research Center (CHRC), Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal.
Biochim Biophys Acta Mol Basis Dis. 2025 Jun;1871(5):167767. doi: 10.1016/j.bbadis.2025.167767. Epub 2025 Mar 4.
Obstructive Sleep Apnea (OSA) is characterized by recurrent-episodes of apneas/hypopneas during sleep, leading to recurrent intermittent-hypoxia and sleep fragmentation. Non-treated OSA can result in cardiometabolic diseases. In this study, we applied a shotgun-proteomics strategy to deeper investigate the red blood cell-(RBC) homeostasis regulation in the context of OSA-severity and their response to six months of positive airway pressure (PAP)-treatment. RBC-samples from patients with Mild/Severe-OSA before/after-PAP treatment and patients as simple-snoring controls were selected. The mass-spectrometry raw-data was analysed by MaxQuant for protein identification/quantification followed by statistical Linear Models-(LM) and Linear Mixed Models-(LMM) to investigate OSA-severity effect and interaction with PAP, respectively. The functional/biological network analysis were performed by DAVID-platform. The results indicated that key-enzymes of the Embden-Meyerhof-Parnas (EMP)-glycolysis and pentose phosphate pathway-(PPP) were differentially changed in Severe-OSA, suggesting that the O-dependent metabolic flux through EMP and PPP maybe compromised in these cells due to severe intermittent hypoxia/reoxygenation-induced oxidative-stress events in these patients. The Rapoport-Luebering-glycolytic shunt showed a significant downregulation across OSA-severity maybe to increase hemoglobin-O affinity to adapt to O low availability in the lung, although EMP-glycolysis showed decreased only in Severe-OSA. Proteins of the immunoproteasome were upregulated in Severe-OSA maybe to respond to severe oxidative-stress. In Mild-OSA, proteins related to the ubiquitination/neddylation-(Ub/Ned)-dependent proteasome system were upregulated. After PAP, proteins of Glycolysis and Ub/Ned-dependent proteasome system showed reactivated in Severe-OSA. In Mild-OSA, PAP induced upregulation of immunoproteasome proteins, suggesting that this treatment may increase oxidative-stress in these patients. Once validated these proteins maybe candidate biomarkers for OSA or OSA-therapy response.
阻塞性睡眠呼吸暂停（OSA）的特征是睡眠期间反复出现呼吸暂停/低通气发作，导致反复间歇性缺氧和睡眠片段化。未经治疗的OSA可导致心脏代谢疾病。在本研究中，我们应用鸟枪法蛋白质组学策略，更深入地研究在OSA严重程度背景下红细胞（RBC）的内稳态调节及其对六个月持续气道正压通气（PAP）治疗的反应。选取了轻度/重度OSA患者在PAP治疗前后以及单纯打鼾对照患者的RBC样本。通过MaxQuant分析质谱原始数据以进行蛋白质鉴定/定量，随后采用统计线性模型（LM）和线性混合模型（LMM）分别研究OSA严重程度的影响以及与PAP的相互作用。通过DAVID平台进行功能/生物网络分析。结果表明，在重度OSA中，糖酵解途径（EMP）和磷酸戊糖途径（PPP）的关键酶发生了差异变化，这表明由于这些患者严重的间歇性缺氧/复氧诱导的氧化应激事件，通过EMP和PPP的氧依赖性代谢通量可能在这些细胞中受到损害。尽管EMP糖酵解仅在重度OSA中降低，但Rapoport-Luebering糖酵解支路在整个OSA严重程度范围内均表现出显著下调，这可能是为了增加血红蛋白与氧的亲和力，以适应肺部低氧供应。免疫蛋白酶体的蛋白质在重度OSA中上调，可能是对严重氧化应激的反应。在轻度OSA中，与泛素化/类泛素化（Ub/Ned）依赖性蛋白酶体系统相关的蛋白质上调。PAP治疗后，糖酵解和Ub/Ned依赖性蛋白酶体系统的蛋白质在重度OSA中显示重新激活。在轻度OSA中，PAP诱导免疫蛋白酶体蛋白质上调，表明这种治疗可能会增加这些患者的氧化应激。一旦这些蛋白质得到验证，它们可能成为OSA或OSA治疗反应的候选生物标志物。
