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, 1863 (2), 621-629

Evening and Morning peroxiredoxin-2 Redox/Oligomeric State Changes in Obstructive Sleep Apnea Red Blood Cells: Correlation With Polysomnographic and Metabolic Parameters

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Evening and Morning peroxiredoxin-2 Redox/Oligomeric State Changes in Obstructive Sleep Apnea Red Blood Cells: Correlation With Polysomnographic and Metabolic Parameters

Amélia Feliciano et al. Biochim Biophys Acta Mol Basis Dis.

Abstract

We have examined the effects of Obstructive Sleep Apnea (OSA) on red blood cell (RBC) proteome variation at evening/morning day time to uncover new insights into OSA-induced RBC dysfunction that may lead to OSA manifestations. Dysregulated proteins mainly fall in the group of catalytic enzymes, stress response and redox regulators such as peroxiredoxin 2 (PRDX2). Validation assays confirmed that at morning the monomeric/dimeric forms of PRDX2 were more overoxidized in OSA RBC compared to evening samples. Six month of positive airway pressure (PAP) treatment decreased this overoxidation and generated multimeric overoxidized forms associated with chaperone/transduction signaling activity of PRDX2. Morning levels of overoxidized PRDX2 correlated with polysomnographic (PSG)-arousal index and metabolic parameters whereas the evening level of disulfide-linked dimer (associated with peroxidase activity of PRDX2) correlated with PSG parameters. After treatment, morning overoxidized multimer of PRDX2 negatively correlated with fasting glucose and dopamine levels. Overall, these data point toward severe oxidative stress and altered antioxidant homeostasis in OSA RBC occurring mainly at morning time but with consequences till evening. The beneficial effect of PAP involves modulation of the redox/oligomeric state of PRDX2, whose mechanism and associated chaperone/transduction signaling functions deserves further investigation. RBC PRDX2 is a promising candidate biomarker for OSA severity and treatment monitoring, warranting further investigation and validation.

Keywords: Biomarkers; Obstructive sleep apnea; Peroxiredeoxin-2; Red blood cells.

Conflict of interest statement

Conflict of interest: The authors have declared no conflict of interest.

Figures

Fig. 1
Fig. 1
2DIGE reference map of Hb-depleted RBC from OSA and Snorers patients collected at evening or morning day time. Differentially abundant protein/proteoforms spots are numbered and indicated with circles on the 2D–gel reference image displayed on the left. Their identity is fully described in Table 3. The acidic form of PRDX2 is one of these differentially proteins showing significantly higher levels of abundance in OSA morning samples as shown on the right.
Fig. 2
Fig. 2
Monitoring the redox/oligomeric states of PRDX2 as classical 2-Cys PRDX. (A) Measurement of PRDX2 redox/oligomeric states in RBCs with NEM analysed by SDS-PAGE under non-reducing condition followed by Western blotting with Ab-PRDX2 or Ab-PRDXSO2/3 (adapted from [17]). NEM is added before and during RBC lyses to prevent peroxidatic cysteines from exogenous-induced oxidation. At non-reducing SDS-PAGE condition, one/two cysteine disulphide bonds linking two PRDX2 monomers into a dimer are kept and migrateat 40 kDa bands, respectively; while PRDX2 dimers composed by fully reduced or fully overoxidized cysteines are denatured into monomers migrating at a unique 20 kDa band (in other cells reduced and overoxidized monomers migrate as two close separated bands). In addition to dimers, PRDXs can form higher order oligomers, predominantly decamers, which are made from reduced, oxidized and/or overoxidized dimers. The four redox/oligomeric states are identified by the Ab-PRDX2. The Ab-PRDXSO2/3 detects those PRDXs forms whose peroxidatic cysteines are overoxidized to SO2/3H acids. Dimers with two dissulfide cysteine linked are thus not detected by this antibody as represented in the Fig. (B) Summarized catalytic cycles of 2-Cys PRDXs adopting different redox/conformation associated functions. Under peroxidase catalytic cycle, 2Cys-PRDX efficiently controls H2O2 concentration through a canonical (re)cycle via thioredoxin(TRX)/NADPH system. Peroxidase activity of 2-Cys PRDXs is not only for oxidant defence but also for H2O2 signaling sensing and/or transduction. In presence of high levels of H2O2, 2-Cys PRDX undergoes a non-peroxidase catalytic cycle or sulphinic (SO2H) or overoxidized cycle that is recycled to active enzyme by sulfiredoxin in the presence of ATP. Reversible oxidation is coupled to circadian rhtythm to 2-Cys PRDX function. Overoxidation of 2-Cys PRDXs allows substantial accumulation of H2O2 for signalling purposes or to confer chaperone function to 2-Cys PRDX under severe oxidative stress. Chaperone activity is attributted to multimeric decameric rings of 2Cys-PRDXs.
Fig. 3
Fig. 3
Western blot validation of 2DIGE proteomics data indicating redox/oligomeric changes in the PRDX2 from OSA evening/morning RBC versus Snorers'. Representative western blots (on the left) of non-reducing SDS-PAGE incubated with Ab PRDX2 (A) or Ab PRDXSO2/3 (B) and graphic representations (on the right)of the relative normalized protein abundance of the different redox/oligomeric forms of PRDX2 identified in the different groups/conditions [Snorers (S) or OSA/evening (E) or morning (M)] calculated from densitometric analysis (see Material & methods). Statistically significant differences (p < 0.05) between groups/conditions are indicated (*).
Fig. 4
Fig. 4
Effect of six month of PAP treatment on the redox/oligomeric state of PRDX2 from morning RBC. Representative western blots images (on the left) of non-reducing SDS-PAGE incubated with Ab PRDX2 (A) or Ab PRDXSO2/3 (B) and graphic representations (on the right) of the relative normalized protein abundance of the different redox/oligomeric forms of PRDX2 identified in the different patients group (Snorers (S), OSA before and after PAP (P) calculated from densitometric analysis (see Material & methods). Statistically significant differences (p < 0.05) between groups/conditions are indicated (*).

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