Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study
Abstract
:1. Introduction
2. Results
2.1. Workflow
2.2. Characterization of Secreted miRNA during Different Oxygen Conditions
2.3. Identification of Secreted miRNA Subsets in Response to Different Oxygen Conditions
2.4. RNA Sequencing from the Mother Cells of the Secretome
2.5. Comparison of Cellular Signaling in Response to O2 Oscillations with Different Amplitudes
2.6. Putative Autocrine Effects of Secreted miRNAs on Cellular mRNA Targets
2.7. Putative Para- and Endocrine Effects
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Exposure to Oxygen Conditions
4.3. Processing of Cell Culture Supernatants
4.4. RNA Isolation for Next-Generation Sequencing
4.5. Small RNA-Sequencing Analysis (Next-Generation Sequencing)
4.6. Quantitative Real-Time PCR
4.7. RNA Sequencing (RNAseq) of Cellular mRNAs
4.8. Data Analysis of qRT-PCR Results and Statistical Evaluation
4.9. Bioinformatical Processing of Data
4.9.1. Extracellular miRNAs
4.9.2. Cellular mRNAs
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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O2 Condition | miRNA | NGS Results NGS (Donors 1–6) | miRNAs with p < 0.1 after qPCR Validation (Incl. Donors 7–12) | |
---|---|---|---|---|
Fold Change (Rel. to 21% O2) | p-Value (<0.05) | Fold Change (Rel. to 21% O2) | ||
5% O2 | hsa-miR-19b-3p | 1.3386 | 0.0049 | 1.3068 |
hsa-miR-222-3p | 0.8383 | 0.0092 | 0.8405 | |
hsa-miR-23a-3p | 1.2177 | 0.0145 | 1.080 | |
hsa-miR-26a-5p | 0.8414 | 0.0185 | 0.8906 | |
hsa-let-7d-3p | 0.7748 | 0.0197 | 1.119 * | |
hsa-miR-21-3p | 1.2995 | 0.0228 | 1.388 | |
hsa-miR-126-5p | 0.8418 | 0.0294 | 1.0665 | |
hsa-miR-181c-3p | 1.3927 | 0.0384 | ||
hsa-miR-1307-5p | 1.3358 | 0.0392 | ||
hsa-miR-92a-3p | 0.8453 | 0.0464 | ||
10% O2 | hsa-miR-4492 | 0.5117 | 0.0365 | |
95% O2 | hsa-miR-181b-5p | 0.6695 | 0.0037 (FDR = 0.096) | 1.097 * |
hsa-miR-181a-5p | 0.7929 | 0.0314 | 0.899 | |
hsa-miR-155-5p | 0.7728 | 0.0322 | 1.033 * | |
hsa-let-7c-5p | 0.7914 | 0.0325 | ||
0–21% O2 | hsa-miR-30b-5p | 1.9702 | 0.0036 | 2.1687 |
hsa-miR-410-3p | 0.5967 | 0.0067 | 0.993 | |
hsa-let-7i-5p | 0.7756 | 0.0130 | 1.190 * | |
hsa-miR-129-5p | 2.7431 | 0.0171 | Ct > 35 | |
hsa-miR-1304-3p | 0.7181 | 0.0189 | ||
hsa-miR-125a-5p | 1.3159 | 0.0229 | 0.956 | |
hsa-miR-654-3p | 1.3576 | 0.0289 | ||
hsa-miR-224-5p | 1.4676 | 0.0290 | ||
hsa-miR-92a-3p | 0.8009 | 0.0339 | ||
hsa-miR-4497 | 0.6404 | 0.0344 | ||
hsa-miR-629-5p | 0.6743 | 0.0377 | ||
hsa-miR-134-5p | 1.2977 | 0.0388 | ||
0–95% O2 | hsa-let-7d-3p | 0.7424 | 0.0026 | 0.8045 |
hsa-miR-155-5p | 0.7668 | 0.0110 | 0.7423 | |
hsa-miR-574-3p | 1.2817 | 0.0154 | 1.1975 | |
hsa-miR-4492 | 0.5622 | 0.0298 | ||
hsa-miR-103a-3p | 0.8102 | 0.0313 | ||
hsa-miR-23a-3p | 1.2192 | 0.0338 | 1.018 | |
hsa-miR-301b-3p | 0.4778 | 0.0339 | ||
hsa-miR-130a-3p | 0.7906 | 0.0391 | ||
hsa-miR-7-5p | 0.8296 | 0.0414 | ||
hsa-miR-26b-5p | 0.8316 | 0.0479 | ||
hsa-miR-98-5p | (0.9409) | (0.1476) | (0.8409) |
O2 Condition | miRNA | Affected Pathways via Target Genes (Reactome Database) |
---|---|---|
5% O2 | hsa-miR-19b-3p (↑) | Signaling by TGFßR, ErbB, SCF-KIT, Wnt. VEGFR-mediated cell proliferation |
hsa-miR-222-3p (↓) | Cell senescence, PI3K/Akt activation, cell cycle, signaling by SCF-KIT, DAP12, FGFR | |
hsa-miR-23a-3p (↑) | IL6-signaling, ATF4 activated genes, signaling by SCF-KIT, EGFR, PI3K/Akt | |
hsa-miR-26a-5p (↓) | Cellular response to stress, gene expression, cellular senescence, cell cycle, DNA damage/telomer stress induction | |
hsa-let-7d-3p (↓) | Anti-cell proliferation, granulopoiesis, T-cell differentiation, cell division (not annotated to exosomes) | |
hsa-miR-21-3p (↑) | Methylation, VEGFA-VEGFR2 signaling, Rho-GTPase signaling, transcriptional regulation by TP53, regulation of actin dynamics | |
hsa-miR-126-5p (↓) | IL-6 signaling, collagen degradation, miRNA biogenesis, PIP3K/Akt, NOTCH | |
hsa-miR-181c-3p (↑) | Calcium activated K + channels, fibrin clot formation, detoxification of ROS, smooth muscle contraction | |
hsa-miR-1307-5p (↑) | Cell–extracellular matrix interaction, mRNA splicing, translocation of GLUT4 to plasma membrane, VEGFA-VEGFR2 signaling, apoptosis, synthesis of very long fatty acids-CoA | |
hsa-miR-92a-3p (↓) | Cell cycle, gene expression, translation | |
10% O2 | hsa-miR-4492 (↓) | Cellular senescence (oxidative stress induced), DAP12 interactions, heme degradation, nuclear events |
95% O2 | hsa-miR-181b-5p (↓) | Cellular senescence and response to stress, DNA fragmentation, apoptosis, signaling by ERBB, NOTCH, calcium-dependent events, IL-1 signaling, interferon signaling, TLR 7/8 |
hsa-miR-181a-5p (↓) | Cell response to stress, signaling by EGFR, ERBB, FGFR, PDGF, RAF/MAPK cascade, signaling by interleukins, immune system, DNA fragmentation | |
hsa-miR-155-5p (↓) | NFKB, B-cell, T-cell receptor, p53, NOD-like receptor, TLR, SMAD, and interleukin (-6) signaling; cellular response to stress, cellular senescence | |
hsa-let-7c-5p (↓) | IL-6, SMAD, SCF-KIT, PI3K/Akt, p53, and NOTCH signaling, respiratory electron transport, cellular senescence, platelet activation, aggregation and degranulation, immune system, ATF6-dependent activation of chaperons | |
0–21% O2 | hsa-miR-30b-5p (↑) | NOTCH, SMAD, TGFßR, and IFNA signaling, intrinsic pathway of apoptosis, cellular senescence, DNA repair, response to oxidative stress |
hsa-miR-410-3p (↓) | Beta-catenin phosphorylation cascade, platelet activation, signaling and aggregation, prolonged ERK activity, CaM pathway, calmodulin induced events | |
hsa-let-7i-5p (↓) | Platelet degranulation, DNA damage/stress-induced senescence, cytokine signaling in immune system, ATF4-activated genes, IFN signaling, PERK regulated gene expression, intrinsic pathway of apoptosis, chromatin organization | |
hsa-miR-129-5p (↑) | RSK activation, sphingolipid metabolism, circadian clock, ERK/MAPK targets, immune system, GABA/NMDA receptor activation, eNOS activation, oxidative stress-induced senescence | |
hsa-miR-1304-3p (↓) | mRNA splicing, ER quality control, biosynthesis of N-glycan precursors, calnexin/calreticulin cycle, Asn-linked N-glycosylation, N-glycan trimming in ER, actin dynamics | |
hsa-miR-125a-5p (↑) | Glycolysis, NGF, SCF-KIT, PDGF, Akt, CTLA4, NOTCH, VEGF, FGFR, TLR, and MAPK signaling | |
hsa-miR-654-3p (↑) | Akt-, IFNG-, FGFR-, EGFR-, PDGF-signaling | |
hsa-miR-224-5p (↑) | SCF-KIT, EGFR, NGF, VEGF, DAP12, Akt, and MAPK signaling: Rho GTPases activate PAKs, intrinsic pathway of apoptosis | |
hsa-miR-92a-3p (↓) | Cell cycle, NOTCH-, Wnt-signaling | |
hsa-miR-4497 (↓) | Rho-GTPases, VEGF and leptin-signaling; response to hypoxia, smooth muscle contraction, platelet degranulation, DNA repair, cytokine signaling in immune system | |
hsa-miR-629-5p (↓) | HATs deacetylate histones, chromatin organization, DNA methylation, NLRP3 inflammasome, tight junctions, cell cycle, apoptosis | |
hsa-miR-134-5p (↑) | Telomere maintenance and extension, cell response to hypoxia, VEGF and interleukin-(-6) signaling, NLRP3 inflammasome, p38MAPK, SOS-mediated signaling, oxygen-dependent proline hydroxylation | |
0–95% O2 | hsa-let-7d-3p (↓) | Transcription, cGMP effects, metabolism of non-coding RNAs, platelet homeostasis |
hsa--miR-155-5p (↓) | See above (as with 95% O2) | |
hsa-miR-574-3p (↑) | Regulation of HIFs, PCP/CE pathway, DSCAM and LICAM interactions, inactivation of Cdc42 and Rac, RhoGTPases activation of NOX, TRAF-dependent IRF activation, Rho GTPases activate IQGAPs | |
hsa--miR-4492 (↓) | Crosslinking of collagen fibrils, heme degradation, nuclear events, GPVI-mediated activation cascade | |
hsa-miR-103a-3p (↓) | siRNA biogenesis, Ca2+ pathway, G-protein activation, opoid signaling, insulin processing, cell cycle | |
hsa-miR-23a-3p (↑) | IL-6 signaling, ERBB, SCF-KIT, EGFR, FGFR, PI3K/Akt, and SMAD signaling, death receptor signaling, Ca2+ pathway | |
hsa-miR-301b-3p (↓) | NF-KB activation for survival, oxygen-dependent proline hydroxylation, Ca2+ pathways, regulated necrosis, IRAK2-mediated activation of TAK1, insuline receptor recycling | |
hsa-miR-130a-3p (↓) | O2-dependent proline hydroxylation, Ca2+ pathways, Wnt, NOTCH, and BMP signaling, glycogen synthesis, circadian clock, regulation of necroptotic cell death, IRAK1 recruits IKK | |
hsa-miR-7-5p (↓) | IRS-mediated signaling, SCF-KIT, EGFR, ERK, NGF, ERBB, Akt, FGFR, and VEGF signaling, immune system, IL-2 signaling, apoptosis | |
hsa-miR-98-5p (↓) | IL-6 and IFN-signaling, cellular stress response and senescence, HATs acetylate histones, glucose transport |
Module | 10% O2 | 21% O2 | 5% O2 | 95% O2 | 0–21% O2 | 0–95% O2 |
---|---|---|---|---|---|---|
M13 | −0.125 | −0.007 | 0.059 | −0.082 | −0.204 | 0.359 |
p = 0.663 | p = 0.980 | p = 0.837 | p = 0.777 | p = 0.473 | p = 0.193 | |
M8 | −0.243 | 0.154 | 0.393 | −0.062 | −0.294 | 0.051 |
p = 0.391 | p = 0.590 | p = 0.149 | p = 0.829 | p = 0.294 | p = 0.861 | |
M0 | −0.227 | 0.203 | 0.156 | 0.042 | −0.271 | 0.098 |
p = 0.424 | p = 0.476 | p = 0.586 | p = 0.886 | p = 0.334 | p = 0.734 | |
M2 | −0.192 | 0.157 | 0.196 | 0.025 | −0.252 | 0.066 |
p = 0.502 | p = 0.583 | p = 0.492 | p = 0.932 | p = 0.372 | p = 0.819 | |
M4 | 0.260 | −0.014 | 0.0278 | −0.0623 | −0.166 | −0.045 |
p = 0.356 | p = 0.961 | p = 0.924 | p = 0.828 | p = 0.562 | p = 0.875 | |
M7 | 0.138 | 0,028 | 0.061 | −0.024 | −0.208 | 0.004 |
p = 0.629 | p = 0.924 | p = 0.833 | p = 0.935 | p = 0.465 | p = 0.988 | |
M14 | −0.173 | −0.029 | −0.008 | 0.325 | −0.136 | 0.021 |
p = 0.546 | p = 0.920 | p = 0.976 | p = 0.243 | p = 0.636 | p = 0.0.942 | |
M6 | −0.243 | 0.069 | 0.113 | −0.049 | 0.075 | 0.037 |
p = 0.390 | p = 0.811 | p = 0.695 | p = 0.864 | p = 0.796 | p = 0.899 | |
M5 | −0.020 | −0.007 | −0.006 | 0.090 | 0.051 | −0.109 |
p = 0.945 | p = 0.982 | p = 0.985 | p = 0.754 | p = 0.859 | p = 0.704 | |
M9 | 0.000 | 0.000 | −0.054 | 0.064 | 0.030 | −0.041 |
p = 0.999 | p = 0.999 | p = 0.853 | p = 0.825 | p = 0.917 | p = 0.888 | |
M1 | −0.022 | −0.015 | 0.044 | −0.013 | 0.023 | −0.017 |
p = 0.940 | p = 0.957 | p = 0.879 | p = 0.964 | p = 0.936 | p = 0.953 | |
M10 | −0.006 | −0.025 | 0.046 | −0.034 | 0.011 | 0.007 |
p = 0.984 | p = 0.931 | p = 0.873 | p = 0.907 | p = 0.970 | p = 0.979 | |
M12 | 0.018 | −0.012 | 0.005 | 0.025 | −0.034 | −0.002 |
p = 0.951 | p = 0.966 | p = 0.986 | p = 0.931 | p = 0.907 | p = 0.995 | |
M11 | 0.009 | 0.000 | 0.023 | −0.027 | −0.023 | 0.017 |
p = 0.975 | p = 0.999 | p = 0.936 | p = 0.925 | p = 0.937 | p = 0.952 | |
M3 | 0.027 | 0.036 | 0.004 | −0.018 | −0.034 | −0.015 |
p = 0.926 | p = 0.902 | p = 0.988 | p = 0.949 | p = 0.907 | p = 0.960 |
O2 Condition | miRNA | Connectivity | |||
---|---|---|---|---|---|
Module | kTotal | kwithin | Kwithin norm | ||
5% O2 | hsa-miR-19b-3p | M1 | 26.839 | 15.669 | 0.948 |
hsa-miR-222-3p | M3 | 22.589 | 7.305 | 0.504 | |
hsa-miR-23a-3p | M1 | 9.843 | 6.341 | 0.384 | |
hsa-miR-26a-5p | M9 | 7.440 | 4.546 | 0.618 | |
hsa-let-7d-3p | M3 | 10.311 | 4.149 | 0.286 | |
hsa-miR-21-3p | M3 | 17.604 | 9.434 | 0.651 | |
hsa-miR-126-5p | M3 | 2.830 | 1.143 | 0.079 | |
hsa-miR-181c-3p | M11 | 0.259 | 0.002 | 0.000 | |
hsa-miR-1307-5p | M1 | 7.606 | 4.265 | 0.258 | |
hsa-miR-92a-3p | M3 | 31.065 | 14.481 | 1.000 | |
10% O2 | hsa-miR-4492 | M3 | 23.365 | 7.392 | 0.510 |
95% O2 | hsa-miR-181b-5p | M1 | 12.731 | 7.049 | 0.426 |
hsa-miR-181a-5p | M10 | 0.852 | 0.412 | 0.088 | |
hsa-miR-155-5p | M9 | 4.433 | 2.099 | 0.285 | |
hsa-let-7c-5p | M3 | 15.407 | 6.221 | 0.430 | |
0–21% O2 | hsa-miR-30b-5p | M5 | 1.718 | 1.051 | 0.361 |
hsa-miR-410-3p | M14 | 2.224 | 1.517 | 0.578 | |
hsa-let-7i-5p | M11 | 0.673 | 0.068 | 0.026 | |
hsa-miR-129-5p | M12 | 0.758 | 0.429 | 0.246 | |
hsa-miR-1304-3p | M6 | 0.831 | 0.122 | 0.009 | |
hsa-miR-125a-5p | M3 | 0.188 | 0.057 | 0.004 | |
hsa-miR-654-3p | M10 | 3.774 | 2.657 | 0.568 | |
hsa-miR-224-5p | M9 | 0.452 | 0.188 | 0.026 | |
hsa-miR-92a-3p | M3 | 31.065 | 14.481 | 1.000 | |
hsa-miR-4497 | M3 | 2.830 | 1.143 | 0.079 | |
hsa-miR-629-5p | M3 | 10.974 | 6.603 | 0.456 | |
hsa-miR-134-5p | M10 | 4.226 | 3.025 | 0.647 | |
0–95% O2 | hsa-let-7d-3p | M3 | 10.311 | 4.149 | 0.286 |
hsa-miR-155-5p | M9 | 4.433 | 2.099 | 0.285 | |
hsa-miR-574-3p | M0 | 1.747 | 0.174 | 0.014 | |
hsa-miR-4492 | M3 | 23.365 | 7.392 | 0.510 | |
hsa-miR-103a-3p | M5 | 3.904 | 2.828 | 0.972 | |
hsa-miR-23a-3p | M1 | 9.843 | 6.341 | 0.384 | |
hsa-miR-301b-3p | M5 | 0.940 | 0.322 | 0.111 | |
hsa-miR-130a-3p | M1 | 3.773 | 2.369 | 0.143 | |
hsa-miR-7-5p | M1 | 26.829 | 13.911 | 0.842 | |
hsa-miR-26b-5p | M5 | 3.067 | 2.454 | 0.843 | |
hsa-miR-98-5p | (M0) | 0.378 | 0.082 | 0.007 |
Module | 10% O2 | 21% O2 | 5% O2 | 95% O2 | 0–21% O2 | 0–95% O2 | Module | 10% O2 | 21% O2 | 5% O2 | 95% O2 | 0–21% O2 | 0–95% O2 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
M87 | 0.17 | −0.16 | 0.39 | −0.48 | 0.18 | −0.05 | M39 | −0.04 | −0.21 | 0.00 | 0.51 | 0.13 | −0.16 |
M16 | 0.09 | 0.05 | −0.03 | −0.35 | 0.18 | 0.19 | M40 | 0.11 | −0.30 | −0.32 | 0.41 | 0.20 | −0.17 |
M73 | 0.19 | 0.04 | −0.05 | −0.26 | 0.09 | −0.09 | M67 | 0.20 | −0.32 | −0.02 | 0.39 | −0.07 | −0.23 |
M90 | 0.14 | 0.07 | 0.13 | −0.33 | 0.10 | 0.02 | M72 | 0.00 | 0.11 | −0.22 | 0.45 | −0.25 | 0.30 |
M12 | 0.03 | 0.18 | 0.04 | −0.29 | −0.03 | 0.04 | M80 | 0.11 | −0.16 | −0.11 | 0.03 | 0.22 | 0.30 |
M70 | 0.18 | 0.09 | 0.03 | −0.25 | −0.03 | −0.01 | M48 | 0.13 | −0.02 | −0.11 | 0.14 | −0.19 | 0.34 |
M82 | 0.09 | 0.01 | 0.28 | −0.27 | 0.09 | 0.20 | M89 | 0.21 | −0.07 | −0.08 | 0.05 | −0.03 | 0.17 |
M71 | 0.20 | 0.02 | 0.18 | −0.15 | −0.02 | −0.01 | M44 | −0.09 | 0.32 | 0.21 | 0.08 | −0.10 | −0.10 |
M30 | 0.14 | 0.00 | 0.26 | −0.13 | −0.05 | 0.13 | M76 | −0.19 | 0.31 | 0.09 | 0.03 | 0.18 | 0.07 |
M6 | 0.04 | 0.04 | 0.19 | −0.11 | −0.07 | 0.16 | M52 | −0.04 | 0.03 | 0.13 | 0.29 | −0.03 | −0.02 |
M8 | 0.19 | 0.05 | 0.24 | −0.30 | 0.37 | −0.21 | M86 | −0.01 | −0.05 | 0.21 | 0.14 | −0.11 | −0.01 |
M84 | 0.16 | 0.15 | 0.10 | −0.23 | 0.28 | −0.23 | M28 | 0.13 | 0.13 | 0.28 | −0.06 | −0.32 | 0.11 |
M47 | 0.05 | −0.04 | 0.08 | −0.34 | 0.45 | 0.23 | M9 | 0.21 | 0.10 | 0.03 | 0.08 | −0.23 | 0.03 |
M63 | −0.02 | −0.18 | 0.18 | −0.19 | 0.33 | 0.11 | M27 | 0.38 | −0.23 | 0.34 | −0.11 | −0.13 | −0.15 |
M91 | −0.01 | −0.16 | 0.46 | −0.18 | 0.56 | −0.39 | M35 | 0.20 | 0.03 | 0.34 | −0.27 | −0.33 | 0.02 |
M54 | −0.19 | 0.10 | 0.16 | 0.04 | 0.39 | −0.33 | M93 | 0.18 | 0.02 | 0.28 | −0.23 | −0.16 | −0.04 |
M41 | −0.18 | 0.12 | −0.05 | 0.03 | 0.32 | −0.06 | M62 | 0.25 | −0.48 | 0.12 | −0.15 | 0.02 | 0.16 |
M79 | −0.10 | 0.03 | −0.06 | 0.15 | 0.38 | −0.17 | M69 | 0.10 | −0.16 | −0.17 | −0.15 | 0.17 | 0.11 |
M19 | 0.17 | −0.25 | 0.04 | −0.08 | 0.44 | −0.06 | M81 | 0.00 | −0.17 | 0.03 | −0.32 | 0.15 | 0.06 |
M64 | 0.03 | −0.25 | −0.08 | −0.02 | 0.54 | −0.05 | M42 | 0.08 | 0.21 | −0.01 | 0.10 | −0.46 | −0.20 |
M21 | 0.22 | −0.10 | −0.09 | −0.08 | 0.30 | −0.02 | M14 | 0.07 | 0.31 | −0.21 | 0.15 | −0.25 | −0.26 |
M55 | 0.13 | −0.01 | −0.22 | −0.04 | 0.44 | −0.14 | M32 | 0.12 | 0.37 | −0.24 | −0.01 | −0.23 | −0.20 |
M85 | −0.25 | 0.14 | −0.28 | 0.43 | −0.03 | 0.02 | M66 | 0.10 | 0.27 | 0.18 | −0.21 | −0.23 | −0.35 |
M15 | −0.11 | −0.14 | 0.03 | 0.34 | −0.19 | 0.06 | M17 | 0.06 | 0.26 | 0.22 | −0.18 | −0.41 | −0.04 |
M31 | −0.33 | −0.14 | −0.01 | 0.29 | 0.02 | 0.06 | M57 | 0.11 | 0.22 | 0.29 | −0.02 | −0.51 | −0.14 |
M60 | −0.29 | 0.07 | 0.02 | 0.26 | −0.02 | 0.00 | M58 | −0.06 | 0.16 | −0.07 | −0.17 | 0.09 | −0.09 |
M43 | −0.30 | 0.13 | −0.21 | 0.39 | −0.52 | 0.01 | M18 | −0.06 | 0.19 | −0.22 | 0.03 | 0.06 | −0.14 |
M29 | 0.04 | −0.02 | 0.05 | 0.24 | −0.50 | 0.16 | M53 | 0.00 | 0.10 | −0.13 | 0.01 | 0.18 | −0.14 |
M25 | 0.10 | −0.01 | −0.06 | 0.31 | −0.42 | −0.05 | M34 | 0.10 | 0.04 | 0.10 | 0.14 | −0.15 | −0.26 |
M50 | −0.01 | 0.11 | −0.01 | 0.15 | −0.46 | 0.01 | M46 | 0.23 | −0.10 | 0.10 | 0.17 | −0.13 | −0.15 |
M23 | −0.03 | 0.05 | −0.13 | 0.10 | −0.51 | 0.28 | M88 | 0.00 | −0.15 | 0.04 | 0.09 | 0.15 | −0.04 |
M49 | −0.12 | −0.01 | −0.11 | 0.20 | −0.40 | 0.04 | M3 | 0.03 | 0.02 | 0.04 | 0.00 | −0.07 | 0.01 |
M92 | −0.14 | 0.05 | −0.07 | 0.16 | −0.52 | 0.16 | M0 | 0.05 | −0.07 | 0.06 | 0.08 | −0.04 | −0.02 |
M51 | −0.33 | 0.08 | −0.40 | 0.19 | 0.00 | 0.18 | M2 | 0.01 | −0.07 | 0.03 | 0.06 | −0.01 | 0.02 |
M68 | −0.15 | 0.09 | −0.38 | −0.06 | 0.11 | 0.12 | M20 | 0.00 | −0.05 | 0.02 | 0.01 | −0.03 | 0.04 |
M65 | −0.42 | −0.12 | 0.03 | −0.05 | 0.06 | 0.30 | M78 | 0.10 | −0.15 | 0.11 | −0.09 | 0.07 | −0.02 |
M4 | −0.31 | 0.04 | −0.15 | 0.05 | −0.17 | 0.22 | M5 | 0.00 | −0.02 | 0.02 | −0.01 | 0.07 | −0.03 |
M74 | −0.23 | −0.12 | −0.03 | −0.01 | −0.01 | 0.13 | M36 | 0.10 | 0.00 | 0.05 | −0.11 | 0.03 | −0.01 |
M94 | −0.25 | −0.04 | −0.10 | 0.13 | −0.11 | 0.07 | M1 | 0.05 | 0.04 | 0.05 | −0.12 | 0.10 | −0.09 |
M37 | −0.11 | −0.43 | −0.22 | 0.28 | 0.24 | 0.11 | M10 | 0.07 | −0.01 | 0.10 | −0.05 | 0.06 | −0.11 |
M77 | −0.16 | −0.39 | −0.14 | 0.17 | 0.29 | 0.28 | M61 | 0.16 | 0.38 | −0.25 | −0.19 | −0.14 | 0.16 |
M13 | −0.16 | −0.12 | −0.15 | 0.00 | 0.28 | −0.02 | M22 | −0.18 | 0.04 | 0.12 | 0.10 | −0.29 | 0.22 |
M59 | −0.22 | −0.20 | −0.17 | −0.14 | 0.48 | 0.18 | M75 | −0.22 | 0.23 | 0.13 | −0.09 | −0.17 | 0.28 |
M33 | 0.06 | −0.33 | −0.12 | 0.34 | −0.30 | 0.10 | M56 | −0.06 | 0.24 | −0.06 | −0.21 | −0.33 | 0.25 |
M38 | 0.06 | −0.33 | −0.01 | 0.37 | −0.25 | −0.02 | M7 | −0.04 | 0.04 | 0.03 | −0.13 | −0.28 | 0.22 |
M26 | 0.13 | −0.33 | −0.28 | 0.54 | −0.10 | 0.08 | M11 | 0.10 | 0.20 | 0.05 | −0.16 | −0.23 | −0.03 |
M83 | −0.10 | −0.22 | −0.19 | 0.53 | −0.12 | −0.01 | M24 | −0.01 | 0.08 | −0.07 | −0.09 | −0.10 | 0.11 |
M45 | −0.16 | 0.22 | −0.05 | −0.06 | −0.15 | 0.04 |
5% O2 | ||
positive correl. | M87 | Microtubule cytoskeleton organization, cell–cell junction assembly, macroautophagy, store-operated calcium entry |
M91 | Regulation of ROS biosynthesis, cytokine production, mitochondrial calcium homeostasis | |
negative correl. | M51 | Membrane organization, cytokinesis, cell division |
10% O2 | ||
negative correl. | M65 | Protein polyubiquitination, cell division |
0–21% O2 | ||
positive correl. | M91 | (see above) |
M54 | Intertypic cell–cell adhesion, positive regulation of stress fiber assembly, reactive nitrogen species metabolism, IL-1, IFNγ production | |
M19 | Glycosylation, lipid biosynthesis, positive regulation of IKß kinase, NFKB signaling, cell-matrix adhesion | |
M64 | VEGF/VEGFR1 pathway, angiopoietin receptor pathway, PI3K/Akt signaling, NTRK2/TRKB signaling | |
M59 | Glycosphingolipid biosynthesis, TOLL-like receptor signaling, apoptosis | |
negative correl. | M43 | Protein sumoylation, ribosome biogenesis |
M29 | Epigenetic regulation of gene expression, base excision repair, telomere maintenance, lipid homeostasis | |
M25 | Mitochondrial outer-membrane permeabilization, fatty acid beta oxidation | |
M50 | Base excision repair, thrombin PAR1 pathway | |
M23 | Vesicle organization, cellular senescence | |
M49 | P53 signaling pathway, protein targeting to lysosome, respiration electron tramsport | |
M92 | Telomere maintenance via telomere lengthening, chaperone mediated protein folding, gene silencing by RNA | |
M42 | Nucleotide excision repair, receptor mediated endocytosis | |
M17 | Proteasome mediated ubiquitin-dependent protein catabolic process, protein exit from ER | |
M57 | Negative regulation of TOR and TORC1 signaling, signaling by FGFR, peroxisome | |
95% O2 | ||
positive correl. | M85 | Response to ionizing radiation, transcriptional activation of mitochondrial biogenesis, respiratory electron transport |
M43 | (see above) | |
M26 | DNA damage/telomere stress-induced senescence, negative regulation of cell development, regulation of oxidative stress-induced intrinsic apoptotic signaling | |
M83 | Response to oxidative stress, DNA damage response, DNA integrity checkpoint signaling, negative regulation of mitochondrial cell cycle, transcriptional regulation by TP53 | |
M39 | Negative regulation of developmental growth, positive regulation of fat cell differentiation, negative regulation of fibroblast prolifertation | |
M40 | Protein mono-, polyubiquitiniation, protein catabolic process, negative regulation of NOTCH signaling | |
M67 | Lipid homeostasis, DNA repair, DNA replication fidelity, telomere maintenance, cholesterol biosynthesis | |
M72 | Regulation of extrinsic apoptosis, DNA repair | |
negative correl. | M87 | (see above) |
0–95% O2 | ||
negative correl. | M91 | (see above) |
95% O2 | 0–21% O2 | |
---|---|---|
miRNAs and Target genes altered in HMVEC-L | hsa-miR-155-5p_(TP53INP1, RAB11FIP2, TAB2, PPM1D, RGP1,TRPS1, ANTXR2, CEBPB, SIPR1) hsa-miR-181a-5p (ZBTB43. CCNK, PRTG, SLC7A11, RLIM, TAB2, BCL2, IPO7, REPS2, N4BP2, DNAJA4, PTBP3, COX15, PARM1, AKIRIN1, CREB1, OGFRL1, NCOA2, TNRC6B, ZDHHC7, MTURN, S1PR1, CREBRF, MTPN, SSB, PRTG) hsa-let-7c-5p (PRTG, MASP1, CEMIP2, SFSWAP, DDI2, SEMA4C, CPSF4, LTN1, TAF98, NIPA1, INTS2, NKAPD1, KIAA0930, MEF2D, BCL2L1, SLF2, NCOA1) | hsa-miR-30b-5p hsa-miR-129-5p hsa-miR-224-5p hsa-miR-125a-5p hsa-miR-654-3p hsa-miR-134-5p hsa-miR-92a-3p hsa-let-7i-5p hsa-miR-629-5p hsa-miR-1304-3p hsa-miR-410-3p corresponding target genes altered in mother cell (see Supplemental Data S4) |
Signaling pathways | Intrinsic apoptosis Cell response to (chemical stress) ESR-mediated signaling KEAP1-NFE2L2 pathway IL4 and IL13 signaling NLRP1 inflammasome Transcriptional activation of mitochondrial biogenesis Circadian clock | Regulation of MECP2 expression and activity RUNX1 regulates expression of tight junctions IL7 signaling Transcription of BIM |
5% O2 | 0–21% O2 |
Signaling by ERBB2, FGFR, GAB1, DAP12, NOTCH, PDGF, NGF PIE/Akt activation Ca2+ pathway Cellular response to stress | Cellular response to stress Oxidative stress-induced senescence (mitotic) cell cycle Signaling by RhoGTPase, NOTCH, Wnt, EGFR, FGFR, DAP12 Chromatin modification Epigenetic regulation of gene expression VEGFR2-mediated cell proliferation Histone methylation, DNA damage/telomere stress-induced senescence Ca2+ pathway |
95% O2 | 0–95% O2 |
Cellular response to stress (oxidative stress-induced) cellular senescence Negative regulation of rRNA expression Immune system Cytokine signaling (IL-6) Apoptosis Activated TLR4 signaling | Oxidative stress-induced senescence PIP3/Akt activation Immune system Ca2+ pathway TP53 regulation of metabolic genes DNA methylation VEGFA/VEGFR2 pathway |
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Share and Cite
Schaubmayr, W.; Hackl, M.; Pultar, M.; Ghanim, B.D.; Klein, K.U.; Schmid, J.A.; Mohr, T.; Tretter, V. Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study. Int. J. Mol. Sci. 2024, 25, 8798. https://doi.org/10.3390/ijms25168798
Schaubmayr W, Hackl M, Pultar M, Ghanim BD, Klein KU, Schmid JA, Mohr T, Tretter V. Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study. International Journal of Molecular Sciences. 2024; 25(16):8798. https://doi.org/10.3390/ijms25168798
Chicago/Turabian StyleSchaubmayr, Wolfgang, Matthias Hackl, Marianne Pultar, Bahil D. Ghanim, Klaus U. Klein, Johannes A. Schmid, Thomas Mohr, and Verena Tretter. 2024. "Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study" International Journal of Molecular Sciences 25, no. 16: 8798. https://doi.org/10.3390/ijms25168798