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
:1. Introduction
2. Materials and Methods
2.1. Participants
2.2. Polysomnography and CPAP Titration Study
2.3. Blood Collection and RNA Isolation
2.4. Whole Genome microRNA Profiles and Analysis by NGS
2.5. Prediction of microRNA Target and Pathway Enrichment
2.6. Analysis of miRNAs by Quantitative Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) in an Independent Validation Cohort
2.7. Determination of Target Gene mRNA Expressions of Isolated PBMCs Using Quantitative RT-PCR
2.8. In Vitro IHR Stimuli in Cell Culture Models
2.9. Transfection with miRNA-15b-5p Mimic/miR-92b-3p Mimic
2.10. Reporter Constructs, Mutagenesis and Luciferase Reporter Assay
2.11. Measurement of Cell Apoptosis by Flow Cytometry Analysis
2.12. Measurement of Intracellular Reactive Oxygen Species (ROS)
2.13. Measurement of MAO Catalytic Activity
2.14. Measurement of Cell Viability by WST-1
2.15. Immunofluorescence Stain
2.16. Statistical Analysis
3. Results
3.1. 22 Differentially Expressed miRs in OSA Patients Versus Healthy Non-Snorers in the NGS Discovery Experiment
3.2. Down-Regulated miR-15b-5p/miR-92b-3p in Treatment-Naïve OSA Patients Versus either PS Subjects or OSA Patient on CPAP Treatment in the Validation Cohort
3.3. Up-Regulated PTGS1 in Treatment-Naive OSA Patients and Depression in the Validation Cohort
3.4. MiR-15b-5p Over-Expression Reversed IHR-Induced Apoptosis, ROS Production, and Target Gene Up-Regulations
3.5. MiR-92b-3p Over-Expression Reversed IHR-Induced Apoptosis, ROS Production, and Target Gene Up-Regulations
3.6. MiR-92b-3p Negatively Regulated PTGS1 in a Direct Manner
3.7. Knockdown of PTGS1 or Overexpression of miR-15b-5p/miR-92b-3p Alleviates IHR-Induced Neuron Cell Injury, Oxidative Stress, and MAOA Hyperactivity via Mediating NF-κB1-SP1 Signaling
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Discovery Cohort | Validation Cohort | ||||||
---|---|---|---|---|---|---|---|
OSA Patients N = 16 | Healthy Subjects N = 8 | p Value | Primary Snoring N = 20 | Treatment-Naïve OSA Patients N = 45 | OSA Patients on CPAP N = 13 | p Value | |
Age, years | 55.2 ± 14.8 | 47.9 ± 13.6 | 0.242 | 44.6 ± 12.6 | 48.5 ± 120.9 | 50.6 ± 7.5 | 0.248 |
Male Sex, n (%) | 12 (75) | 8 (100) | 0.121 | 12 (60) | 34 (75.6) | 11 (84.6) | 0.252 |
BMI, kg/m2 | 27.3 ± 3.7 | 25.0 ± 3.2 | 0.144 | 25.1 ± 3.6 | 26.4 ± 3.4 | 27.3 ± 2.9 | 0.173 |
AHI, events/hour | 44.5 ± 24.5 | NA | 2.7 ± 1.8 | 54.8 ± 19.2 | 62.5 ± 23.3 | <0.001 | |
ODI, events/hour | 25.8 ± 27.5 | NA | 0.8 ± 0.2 | 41.9 ± 24.7 | 44.9 ± 29.4 | <0.001 | |
Mean SaO2, % | 95.0 ± 2.4 | NA | 96.1 ± 1.6 | 93.7 ± 2.5 | 93.7 ± 2.5 | 0.001 | |
Nadir SaO2, % | 78.5 ± 13.2 | NA | 89.1 ± 3.7 | 70.4 ± 15.8 | 72.5 ± 13 | <0.001 | |
Snoring index, counts/hour | 359.3 ± 278.4 | NA | 129.7 ± 147.6 | 374.7 ± 200.1 | 315.2 ± 189.5 | <0.001 | |
Smoking, n (%) | 7 (43.8) | 3 (37.5) | 0.77 | 4 (20) | 11 (24.4) | 4 (30.8) | 0.78 |
Alcoholism, n (%) | 0 (0) | 0 (0) | 1.0 | 0 (0) | 0 (0) | 1 (7.7) | 0.138 |
Cholesterol, mg/dl | 212.1 ± 58.6 | 183.2 ± 41.5 | 0.346 | 186.7 ± 41.8 | 200.1 ± 38.6 | 188.4 ± 38.6 | 0.375 |
Triglycerides, mg/dl | 158 ± 89.8 | 75.6 ± 29.1 | 0.071 | 118.7 ± 71.4 | 170.1 ± 82.6 | 143.8 ± 66.6 | 0.063 |
Hypertension, n (%) | 4 (25) | 2 (25) | 1.0 | 3 (15) | 17 (37.8) | 8 (61.5) | 0.023 |
Diabetes mellitus, n (%) | 1 (6.3) | 1 (12.5) | 0.602 | 1 (5) | 7 (15.6) | 1 (7.7) | 0.419 |
Heart disease, n (%) | 2 (12.5) | 0 (0) | 0.296 | 2 (10) | 2 (4.4) | 1 (7.7) | 0.686 |
Stroke, n (%) | 1 (6.3) | 1 (12.5) | 0.602 | 1 (5) | 0 (0) | 0 (0) | 0.23 |
COPD, n (%) | 2 (12.5) | 1 (12.5) | 1.0 | 2 (10) | 2 (4.4) | 2 (15.4) | 0.386 |
CKD, n (%) | 0 (0) | 0 (0) | 1.0 | 1 (5) | 0 (0) | 0 (0) | 0.23 |
Depression, n (%) | 6 (37.5) | 1 (12.5) | 0.204 | 8 (40) | 12 (26.7) | 2 (15.4) | 0.298 |
ID | Description | Gene Ratio * | Bg Ratio # | Adjusted p Value | q Value | Excluded miRNA |
---|---|---|---|---|---|---|
hsa04218 | Cellular senescence | 85/1996 | 156/8105 | 1.19 × 10−13 | 7.06 × 10−14 | hsa-miR-29c-5p |
hsa04390 | Hippo signaling pathway | 83/1996 | 157/8105 | 1.77 × 10−12 | 1.05 × 10−12 | hsa-miR-29c-5p |
hsa04110 | Cell cycle | 69/1996 | 124/8105 | 6.62 × 10−12 | 3.94 × 10−12 | 22 miRs involved |
hsa04520 | Adherens junction | 44/1996 | 71/8105 | 1.27 × 10−9 | 7.53 × 10−10 | hsa-miR-29c-5p |
hsa04933 | AGE-RAGE signaling pathway in diabetic complications | 54/1996 | 100/8105 | 1.06 × 10−8 | 6.28 × 10−9 | 22 miRs involved |
hsa04150 | mTOR signaling pathway | 74/1996 | 155/8105 | 1.06 × 10−8 | 6.28 × 10−9 | hsa-miR-29c-5p |
hsa04350 | TGF-beta signaling pathway | 51/1996 | 94/8105 | 1.6 × 10−8 | 9.49 × 10−9 | 22 miRs involved |
hsa04141 | Protein processing in endoplasmic reticulum | 78/1996 | 171/8105 | 2.97 × 10−8 | 1.76 × 10−8 | hsa-miR-29c-5p |
hsa04115 | p53 signaling pathway | 42/1996 | 73/8105 | 3.89 × 10−8 | 2.31 × 10−8 | hsa-miR-29c-5p |
hsa04510 | Focal adhesion | 87/1996 | 201/8105 | 6.84 × 10−8 | 4.06 × 10−8 | hsa-miR-29c-5p |
hsa04068 | FoxO signaling pathway | 63/1996 | 131/8105 | 7.04 × 10−8 | 4.18 × 10−8 | hsa-miR-29c-5p |
hsa04550 | Signaling pathways regulating pluripotency of stem cells | 67/1996 | 143/8105 | 8.35 × 10−8 | 4.96 × 10−8 | 22 miRs involved |
hsa04120 | Ubiquitin mediated proteolysis | 64/1996 | 140/8105 | 4.24 × 10−7 | 2.52 × 10−7 | hsa-miR-29c-5p |
hsa01522 | Endocrine resistance | 49/1996 | 98/8105 | 4.95 × 10−7 | 2.94 × 10−7 | hsa-miR-29c-5p |
hsa04010 | MAPK signaling pathway | 112/1996 | 294/8105 | 1.37 × 10−6 | 8.13 × 10−7 | 22 miRs involved |
hsa04668 | TNF signaling pathway | 53/1996 | 112/8105 | 1.38 × 10−6 | 8.17 × 10−7 | hsa-miR-29c-5p, has-miR-4433b-3p, hsa-miR-574-3p |
hsa04152 | AMPK signaling pathway | 55/1996 | 120/8105 | 2.85 × 10−6 | 1.69 × 10−6 | hsa-miR-574-3p |
hsa04810 | Regulation of actin cytoskeleton | 87/1996 | 218/8105 | 3.01 × 10−6 | 1.79 × 10−6 | 22 miRs involved |
hsa04211 | Longevity regulating pathway | 44/1996 | 89/8105 | 3.01 × 10−6 | 1.79 × 10−6 | hsa-miR-29c-5p, has-miR-4433b-3p, hsa-miR-574-3p |
hsa04151 | PI3K-Akt signaling pathway | 128/1996 | 354/8105 | 4.15 × 10−6 | 2.47 × 10−6 | 22 miRs involved |
hsa05202 | Transcriptional mis-regulation in cancer | 78/1996 | 192/8105 | 4.62 × 10−6 | 2.74 × 10−6 | hsa-miR-29c-5p, hsa-miR-574-3p |
hsa04722 | Neurotrophin signaling pathway | 53/1996 | 119/8105 | 1.01 × 10−5 | 6.01 × 10−6 | 22 miRs involved |
hsa05417 | Lipid and atherosclerosis | 83/1996 | 215/8105 | 2.01 × 10−5 | 1.19 × 10−5 | hsa-miR-29c-5p |
hsa04071 | Sphingolipid signaling pathway | 52/1996 | 119/8105 | 2.38 × 10−5 | 1.42 × 10−5 | hsa-miR-4433b-3p |
hsa04530 | Tight junction | 68/1996 | 169/8105 | 2.9 × 10−5 | 1.72 × 10−5 | hsa-miR-29c-5p |
hsa04919 | Thyroid hormone signaling pathway | 52/1996 | 121/8105 | 4.14 × 10−5 | 2.46 × 10−5 | 22 miRs involved |
hsa04144 | Endocytosis | 92/1996 | 252/8105 | 7.94 × 10−5 | 4.72 × 10−5 | 22 miRs involved |
hsa04710 | Circadian rhythm | 19/1996 | 31/8105 | 8.95 × 10−5 | 5.32 × 10−5 | hsa-miR-223-5p, hsa-miR-29c-5p, hsa-miR-574-3p |
hsa04310 | Wnt signaling pathway | 65/1996 | 166/8105 | 1.13 × 10−4 | 6.69 × 10−5 | hsa-miR-29c-5p |
hsa04910 | Insulin signaling pathway | 55/1996 | 137/8105 | 2.02 × 10−4 | 1.2 × 10−4 | hsa-miR-29c-5p, hsa-miR-574-3p |
hsa05010 | Alzheimer disease | 124/1996 | 369/8105 | 2.32 × 10−4 | 1.38 × 10−4 | 22 miRs involved |
hsa04210 | Apoptosis | 54/1996 | 136/8105 | 3.08 × 10−4 | 1.83 × 10−4 | hsa-miR-29c-5p, hsa-miR-574-3p |
hsa04066 | HIF-1 signaling pathway | 45/1996 | 109/8105 | 4.05 × 10−4 | 2.4 × 10−4 | 22 miRs involved |
hsa04340 | Hedgehog signaling pathway | 27/1996 | 56/8105 | 4.85 × 10−4 | 2.88 × 10−4 | hsa-miR-29c-5p, hsa-miR-574-3p |
hsa04015 | Rap1 signaling pathway | 75/1996 | 210/8105 | 8.14 × 10−4 | 4.84 × 10−4 | hsa-miR-4433b-3p |
hsa04935 | Growth hormone synthesis, secretion and action | 47/1996 | 119/8105 | 9.53 × 10−4 | 5.66 × 10−4 | 22 miRs involved |
hsa04657 | IL-17 signaling pathway | 39/1996 | 94/8105 | 9.53 × 10−4 | 5.66 × 10−4 | hsa-miR-223-5p, hsa-miR-29c-5p, hsa-miR-574-3p |
hsa04962 | Vasopressin-regulated water reabsorption | 21/1996 | 44/8105 | 2.797 × 10−3 | 1.662 × 10−3 | hsa-miR-223-5p, hsa-miR-4433b-3p |
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Chen, Y.-C.; Hsu, P.-Y.; Su, M.-C.; Chen, T.-W.; Hsiao, C.-C.; Chin, C.-H.; Liou, C.-W.; Wang, P.-W.; Wang, T.-Y.; Lin, Y.-Y.; et al. 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 2021, 10, 1854. https://doi.org/10.3390/antiox10111854
Chen Y-C, Hsu P-Y, Su M-C, Chen T-W, Hsiao C-C, Chin C-H, Liou C-W, Wang P-W, Wang T-Y, Lin Y-Y, et al. 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. 2021; 10(11):1854. https://doi.org/10.3390/antiox10111854
Chicago/Turabian StyleChen, Yung-Che, 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, and et al. 2021. "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 10, no. 11: 1854. https://doi.org/10.3390/antiox10111854
APA StyleChen, Y.-C., Hsu, P.-Y., Su, M.-C., Chen, T.-W., Hsiao, C.-C., Chin, C.-H., Liou, C.-W., Wang, P.-W., Wang, T.-Y., Lin, Y.-Y., Lee, C.-P., & Lin, M.-C. (2021). 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, 10(11), 1854. https://doi.org/10.3390/antiox10111854