MicroRNA Sequencing Analysis in Obstructive Sleep Apnea and Depression: Anti-Oxidant and MAOA-Inhibiting Effects of miR-15b-5p and miR-92b-3p through Targeting PTGS1-NF-κB-SP1 Signaling

Abstract

The aim of this study was to identify novel microRNAs related to obstructive sleep apnea (OSA) characterized by intermittent hypoxia with re-oxygenation (IHR) injury. Illumina MiSeq was used to identify OSA-associated microRNAs, which were validated in an independent cohort. The interaction between candidate microRNA and target genes was detected in the human THP-1, HUVEC, and SH-SY5Y cell lines. Next-generation sequencing analysis identified 22 differentially expressed miRs (12 up-regulated and 10 down-regulated) in OSA patients. Enriched predicted target pathways included senescence, adherens junction, and AGE-RAGE/TNF-α/HIF-1α signaling. In the validation cohort, miR-92b-3p and miR-15b-5p gene expressions were decreased in OSA patients, and negatively correlated with an apnea hypopnea index. PTGS1 (COX1) gene expression was increased in OSA patients, especially in those with depression. Transfection with miR-15b-5p/miR-92b-3p mimic in vitro reversed IHR-induced early apoptosis, reactive oxygen species production, MAOA hyperactivity, and up-regulations of their predicted target genes, including PTGS1, ADRB1, GABRB2, GARG1, LEP, TNFSF13B, VEGFA, and CXCL5. The luciferase assay revealed the suppressed PTGS1 expression by miR-92b-3p. Down-regulated miR-15b-5p/miR-92b-3p in OSA patients could contribute to IHR-induced oxidative stress and MAOA hyperactivity through the eicosanoid inflammatory pathway via directly targeting PTGS1-NF-κB-SP1 signaling. Over-expression of the miR-15b-5p/miR-92b-3p may be a new therapeutic strategy for OSA-related depression.

“Leaky Gut” as a Keystone of the Connection between Depression and Obstructive Sleep Apnea Syndrome? A Rationale and Study Design

“…At the same time, they showed increased LBP and I-FABP levels indicating more bacterial translocation and 'leaky gut' [56]. Furthermore, increased intestinal permeability in non-obese males with OSA (as compared to non-OSA subjects) showed significant associations with inflammatory mediators (serum IL-1β) [53], and zonulin levels in OSA patients correlated positively with some metabolic, inflammation and hepatic parameters [6]. Interestingly, OSAS children showed increased severity of inflammation and gut barrier damage-related strains as compared to healthy population [57].…”

“…Its prevalence is increasing worldwide [3,4]. Metabolic disorders are in particular closely associated with OSA syndrome (OSAS) which is a chronic disorder characterized by intermittent hypoxia during sleep with re-oxygenation injury [5,6]. In fact, more than two thirds of people with OSA is at least overweight and weight loss helps reduce OSA severity or attenuate other symptoms (reviewed in [7]).…”

Associated factors of primary snoring and obstructive sleep apnoea in patients with sleep bruxism: A questionnaire study

“…40 Previous studies focusing on genetic factors also found two microRNAs (viz., miR-15b-5p and miR-92b-3p) that may modify OSA-related depression. 41 On the other hand, compared with individuals without SB, SB patients were found to have higher scores of depression. 42 SB has long been known to be regulated centrally, and depression is considered a potential aetiology of SB 16 .…”

“…Available evidence suggests that OSA may lead to the development or exacerbation of depressive symptoms by initiating or amplifying the pathologic processes of cerebral small vessel disease and blood–brain barrier dysfunction 40 . Previous studies focusing on genetic factors also found two microRNAs (viz., miR‐15b‐5p and miR‐92b‐3p) that may modify OSA‐related depression 41 . On the other hand, compared with individuals without SB, SB patients were found to have higher scores of depression 42 .…”

Micro-RNA in obstructive sleep apnoea: biomarker of cardiovascular outcome?

“…The potential of miR-499 as a biomarker of OSA has been also evaluated, with higher levels identified in a population with OSA than in control patients [41 ▪ ]. Similarly, Chen et al [42 ▪ ] identified 22 differentially expressed miRNAs that regulate important genomic pathways, such as cellular senescence, the cell cycle and adherents junctions. Furthermore, the miRNA profile was characterized by IH with reoxygenation injury.…”