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

Yung-Che Chen; Po-Yuan Hsu; Mao-Chang Su; Ting-Wen Chen; Chang-Chun Hsiao; Chien-Hung Chin; Chia-Wei Liou; Po-Wen Wang; Ting-Ya Wang; Yong-Yong Lin; Chiu-Ping Lee; Meng-Chih Lin

doi:10.3390/antiox10111854

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

Antioxidants (Basel). 2021 Nov 22;10(11):1854. doi: 10.3390/antiox10111854.

Authors

Yung-Che Chen^{1

2

3}, Po-Yuan Hsu¹, Mao-Chang Su^{1

2

4}, Ting-Wen Chen^{5

6}, Chang-Chun Hsiao^{1

7}, Chien-Hung Chin^{1

3}, Chia-Wei Liou⁸, Po-Wen Wang^{5

6}, Ting-Ya Wang¹, Yong-Yong Lin¹, Chiu-Ping Lee¹, Meng-Chih Lin^{1

2

3}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
² Department of Medicine, College of Medicine, Chang Gung University, Taouyan 33302, Taiwan.
³ Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
⁴ Department of Respiratory Therapy, Chang Gung University of Science and Technology, Chia-yi 613016, Taiwan.
⁵ Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan.
⁶ Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan.
⁷ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taouyan 33302, Taiwan.
⁸ Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

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.

Keywords: PTGS1; depression; miR-15b; miR-92b; microRNA; next generation sequencing; obstructive sleep apnea.

Abstract

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