Reduced Expression of Selected Exosomal MicroRNAs Is Associated with Poor Outcomes in Patients with Acute Stroke Receiving Reperfusion Therapy—Preliminary Study
Abstract
1. Introduction
2. Results
2.1. Study Design
2.2. DEmiRNA Identification
2.3. Identifying DEmiRNA Related to Stroke Patient’s Functional Outcome
2.4. Estimating Gene Targets for Differentially Expressed miRNAs and Their Enrichment Analysis
2.4.1. Estimating Gene Targets for DEmiRNA in Patients Receiving rt-PA/MT Treatment
2.4.2. Estimating Gene Targets for DEmiRNA in Patients Categorized Based on the 10-Day mRS Score
2.4.3. Estimating Gene Targets for DEmiRNA in Patients Categorized Based on the 90-Day mRS Score
2.5. Analysis of the Enriched Pathways Targeted by DEmiRNAs Using Various Databases, Including PANTHER, Disease Alliance, HALLMARK, WIKI, KEGG, and Elsevier
2.5.1. Analysis of the Enriched Pathways Targeted by DEmiRNAs in the Patients Receiving rt-PA/MT Treatment
2.5.2. Analysis of the Enriched Pathways Targeted by DEmiRNAs in Patients Categorized Based on the 10-Day mRS Score
2.5.3. Analysis of the Enriched Pathways Targeted by DEmiRNAs in Patients Categorized Based on the 90-Day mRS Score
3. Discussion
Limitations
4. Materials and Methods
4.1. Inclusion Criteria
4.2. Serum Sampling
4.3. Exosome Isolation from Serum
4.4. Exosomal miRNA qPCR/RT
4.5. MiRNAs Quantification and Differential Expression Analysis
4.6. Estimation of DEmiRNAs Gene Targets and Enrichment Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ABL2 | Abelson Tyrosine-Protein Kinase 2 |
ACTR2 | Actin-Related Protein 2 |
AGO4 | Argonaute RISC Component 4 |
APP | Amyloid Precursor Protein |
ARHGAP12 | Rho GTPase-Activating Protein 12 |
ATG14 | Autophagy-Related Protein 14 |
BTG2 | BTG Anti-Proliferation Factor 2 |
BTN3A3 | Butyrophilin Subfamily 3 Member A3 |
BZW1 | Basic Leucine Zipper and W2 Domains 1 |
CAPZA2 | Capping Actin Protein of Muscle Z-Line Subunit Alpha 2 |
CCND1 | Cyclin D1 |
CRIM1 | Cysteine-Rich Motor Neuron 1 |
CRKL | CT10 Regulator of Kinase |
DNAJC10 | DnaJ Heat Shock Protein Family Member C10 |
EIF2B2 | Eukaryotic Translation Initiation Factor 2B Subunit Beta |
EIF4G2 | Eukaryotic Translation Initiation Factor 4 Gamma 2 |
FZD9 | Frizzled Class Receptor 9 |
HSPA8 | Heat Shock Protein Family A (Hsp70) Member 8 |
ITGA2 | Integrin Subunit Alpha 2 |
KIF23 | Kinesin Family Member 23 |
LAMC1 | Laminin Subunit Gamma 1 |
MAP2K3 | Mitogen-Activated Protein Kinase 3 |
MCL1 | Myeloid Cell Leukemia 1 |
PMAIP1 | Phorbol-12-Myristate-13-Acetate-Induced Protein 1 |
PTEN | Phosphatase and Tensin Homolog |
RAB3IP | RAB3A Interacting Protein |
RBM12B | RNA Binding Motif Protein 12B |
RFK | Riboflavin Kinase |
RPL14 | Ribosomal Protein L14 |
RPRD2 | Regulation Of Nuclear Pre-MRNA Domain Containing 2 |
SHOC2 | Leucine-Rich Repeat Protein SHOC2 |
SIK1 | Salt-Inducible Kinase 1 |
SKI | c-ski protooncogene |
SLC28A1 | Solute Carrier Family 28 Member 1 |
SMAD7 | SMAD Family Member 7 |
SOCS5 | Suppressor Of Cytokine Signaling 5 |
SPRED1 | Sprouty-Related, EVH1 Domain-Containing Protein 1 |
TXNIP | Thioredoxin Interacting Protein |
VEGFR2 | Vascular Endothelial Growth Factor Receptor 2 |
WNK3 | WNK Lysine Deficient Protein Kinase 3 |
YTHDC1 | YTH Domain Containing 1 |
ZMAT3 | Zinc Finger Matrin-Type 3 |
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Baseline Demographic and Clinical Characteristics | |
---|---|
Cohort, n | 72 |
Age, mean., med. [ref.] | 70, 72.5 [35–93] |
Gender M/F | 37/35 |
BMI (kg/m2), med. [ref.] | 27.5 [17–36] |
Medical history | |
Atrial Fibrillation | 28 (39%) |
Arterial Hypertension | 65 (90%) |
Diabetes Mellitus | 25 (35%) |
Coronary Artery Disease | 21 (29%) |
Peripheral Artery Disease | 25 (35%) |
Lipid Disorders | 31 (43%) |
Smoking | 18 (25%) |
Stroke Characteristics | |
Occluded artery | |
Left Middle cerebral artery | 23 (32%) |
Right Middle cerebral artery | 14 (19%) |
Left Internal carotid artery | 4 (6%) |
Basilar artery | 1 (1%) |
No thrombus | 30 (42%) |
Circulation territory (Oxfordshire community stroke project) | |
Total anterior cerebral artery | 20 (28%) |
Partial anterior cerebral artery | 23 (32%) |
Lacunar infarct | 23 (32%) |
Posterior circulation infarct | 6 (8%) |
Stroke etiology (TOAST-trial of ORG 10172 in acute stroke treatment) | |
Atherosclerosis | 23 (32%) |
Cardioembolism | 29 (40%) |
Small vessel occlusion | 14 (19%) |
Unknown/others origin of stroke | 6 (8%) |
Cohort Treatment | |
Antithrombotic therapy (aspirin) | 19 (26%) |
Reperfusion therapy | |
rt-Pa | 17 (24%) |
MT | 9 (12.5%) |
rt-Pa + MT | 27 (27.5%) |
Mechanical Thrombectomy | |
MT (n = 36) Stent retriever Aspiration | 25 (69%) 11 (31%) |
Stroke onset-groin puncture, mean [ref.] min. | 262 [140–360] |
TICI (Treatment in cerebral infarction) | |
0 | 4 (11%) |
1 | 0 (0%) |
2b | 1 (3%) |
2c | 2 (5.5%) |
3 | 29 (80.5%) |
Successful recanalization (TICI 2b/2c/3) | 32 (89%) |
Blood Tests | |
Day 1 [normal range] | |
RBC_1 | 4.33 × 106/µL [4.00–5.00] |
WBC_1 | 9.68 × 103/µL [4.00–10.00] |
Lymphocyte_1 | 1.77 × 103/µL [1.00–4.50] |
Neutrophile_1 | 6.11 × 103/µL [2.00–6.14] |
Basophile_1 | 0.03 × 103/µL [0.00–0.10] |
Eosinophile_1 | 0.07 × 103/µL [0.05–0.50] |
PLT_1 | 200 × 103/µL [135–350] |
HCT_1 | 37.93% [36.00–47.00] |
Hb_1 | 13.19 g/dL [12.00–16.00] |
creatinine | 2.39 mg/dL [0.51–0.95] |
eGFR | 73 mL/min/1.73 m2 [>60] |
CRP | 13 mg/L [<5.0] |
Day 10 [normal range] | |
RBC_10 | 4.36 × 106/µL [4.00–5.00] |
WBC_10 | 7.94 × 106/µL [4.00–10.00] |
PLT_10 | 272 × 103/µL [135–350] |
HCT_10 | 38.17% [36.00–47.00] |
Hb_10 | 13.12 g/dL [12.00–16.00] |
Functional Outcome | |
NIHSS day 1, med. [ref.] | 9 [0–28] |
NIHSS day 2 | 4 [0–28] |
NIHSS day 10 | 2 [0–24] |
10-day mRS, med. [ref.] | 2 [0–6] |
90-day mRS | 1 [0–6] |
TREATMENT (Mean Ct level) | ||||||||
---|---|---|---|---|---|---|---|---|
miRNA | Aspirin | rt-PA | MT | rt-PA + MT | ||||
Day | Day | Day | Day | |||||
1st | 10th | 1st | 10th | 1st | 10th | 1st | 10th | |
let-7g-5p | 4.90 | 4.83 | 5.08 | 4.80 | 5.02 | 4.45 | 5.21 | 4.60 |
miR-15a-5p | −0.07 | −0.17 | −0.17 | −0.29 | −0.43 | −0.71 | −0.08 | −0.99 * |
miR-16-5p | −1.02 | −1.30 | −1.15 | −1.29 | −1.23 | −1.38 | −0.76 | −1.80 * |
miR-17-5p | 1.15 | 1.17 | 1.25 | 1.10 | 1.40 | 0.67 | 1.46 | 0.61 * |
miR-20a-5p | 1.22 | 1.10 | 1.37 | 1.07 | 1.21 | 0.82 | 1.73 | 0.78 * |
miR-21-5p | 0.64 | 0.78 | 0.87 | 0.68 | 0.27 | −0.16 | 0.38 | −0.10 |
miR-23a-3p | 0.99 | 0.90 | 0.72 | 0.53 | 0.66 | −0.14 | 0.53 | 0.22 |
miR-26b-5p | −0.09 | 0.00 | 0.32 | −0.54 | 0.11 | −0.78 | 0.17 | −0.54 |
miR-30b-5p | 1.37 | 1.13 | 1.41 | 1.06 | 1.58 | 0.97 | 1.78 | 1.05 |
miR-92a-3p | −0.51 | −0.65 | −0.58 | −0.80 | −0.70 | −0.71 | −0.40 | −0.96 * |
miR-93-5p | 3.87 | 3.52 | 3.98 | 3.67 | 3.75 | 3.46 | 3.89 | 3.12 * |
miR-103a-3p | 3.29 | 2.77 | 3.06 | 3.01 | 3.23 | 2.68 | 3.11 | 2.49 |
miR-107 | 3.66 | 3.21 | 4.09 | 3.47 | 3.93 | 3.18 | 4.17 | 3.62 |
miR-125b-5p | 5.84 | 5.86 | 6.11 | 5.59 | 5.46 | 4.90 | 5.24 | 4.77 |
miR-126-3p | 0.25 | 0.48 | 0.16 | 0.11 | −0.24 | −1.06 | 0.17 | 0.03 |
miR-130a-3p | 3.17 | 3.69 | 3.25 | 3.33 | 3.59 | 2.93 | 2.86 | 2.57 |
miR-142-3p | 2.11 | 2.27 | 1.62 | 2.21 | 1.86 | 1.38 | 2.53 | 1.76 |
miR-143-3p | 3.45 | 3.55 | 3.99 | 3.17 | 3.44 | 2.15 | 2.96 | 2.65 |
miR-148a-3p | 3.61 | 3.73 | 3.77 | 3.74 | 3.31 | 3.05 | 3.09 | 2.80 |
miR-150-5p | 2.25 | 2.20 | 2.22 | 1.88 | 3.81 | 1.97 | 2.37 | 2.03 |
miR-152-3p | 4.31 | 4.64 | 4.25 | 5.21 * | 4.94 | 3.67 | 4.24 | 3.80 |
miR-153-3p | 8.46 | 8.06 | 8.60 | 8.48 | 7.72 | 7.40 | 8.32 | 8.49 * |
miR-181c-5p | 6.81 | 6.99 | 6.72 | 6.73 | 6.94 | 6.10 | 7.00 | 6.92 |
miR-185-5p | 2.07 | 2.03 | 2.02 | 2.05 | 1.97 | 1.99 | 2.45 | 1.74 * |
miR-186-5p | 4.14 | 4.06 | 4.08 | 3.79 | 4.11 | 3.64 | 4.32 | 3.72 * |
miR-193b-3p | 6.82 | 6.44 | 6.64 | 6.43 | 5.63 | 5.82 | 5.87 | 5.96 |
miR-193a-5p | 4.88 | 5.24 | 5.27 | 4.62 | 4.28 | 2.82 | 3.86 | 4.20 |
miR-199a-3p | 2.69 | 3.02 | 2.89 | 2.62 | 3.04 | 1.78 | 2.53 | 2.37 |
miR-205-5p | 2.13 | 1.96 | 0.39 | 0.52 | 2.27 | 1.34 | 1.43 | 1.07 |
miR-210-3p | 4.22 | 4.68 | 4.92 | 4.85 | 4.21 | 4.28 | 4.62 | 4.05 * |
miR-221-3p | −0.01 | 0.21 | −0.24 | −0.41 | −0.33 | −0.91 | −0.34 | −0.47 |
miR-222-3p | 6.27 | 6.43 | 6.48 | 6.33 | 5.98 | 5.23 | 6.00 | 5.24 * |
miR-223-3p | −0.87 | −0.85 | −0.61 | −1.09 | −0.65 | −1.84 | −0.62 | −1.16 |
miR-224-5p | 9.50 | 8.90 | 9.32 | 8.60 | 8.74 | 7.21 | 8.72 | 8.08 |
miR-326 | 2.34 | 2.86 | 2.18 | 2.04 | 2.40 | 1.93 | 2.12 | 2.09 |
miR-339-5p | 3.60 | 3.74 | 3.86 | 3.54 | 3.70 | 3.02 | 3.53 | 3.07 |
miR-342-3p | 5.20 | 5.26 | 5.51 | 5.45 | 5.77 | 4.76 | 5.56 | 5.06 |
miR-361-5p | 5.79 | 5.71 | 5.80 | 5.50 | 5.63 | 4.57 | 5.67 | 5.16 |
miR-376a-3p | 5.98 | 5.60 | 5.58 | 5.28 | 5.24 | 4.85 | 5.63 | 6.23 |
miR-423-5p | 1.60 | 1.54 | 1.77 | 1.66 | 1.62 | 1.81 | 1.53 | 1.43 |
miR-424-5p | 2.62 | 2.22 | 2.80 | 2.49 | 2.68 | 1.83 | 2.38 | 1.56 * |
miR-484 | 1.47 | 1.50 | 1.55 | 1.62 | 1.67 | 1.25 | 1.48 | 1.20 |
miR-486-5p | −1.46 | −1.62 | −1.42 | −1.29 | −1.60 | −1.28 | −1.08 | −1.80 * |
miR-505-3p | 6.71 | 6.77 | 6.17 | 6.70 | 4.79 | 5.66 | 6.07 | 5.25 |
miR-576-5p | 2.97 | 2.78 | 2.82 | 2.35 | 2.76 | 4.25 | 3.34 | 2.81 |
miR-652-3p | 3.70 | 3.68 | 3.79 | 3.48 | 3.64 | 3.21 | 3.73 | 3.46 |
miR-744-5p | 2.36 | 2.76 | 2.66 | 2.13 | 2.14 | 1.45 | 2.70 | 2.64 |
TREATMENT (deltaCt) | ||||
---|---|---|---|---|
miRNA | Aspirin | rt-PA | MT | rt-PA + MT |
let-7g-5p | −0.0694 | −0.2738 | −0.5620 | −0.6083 |
miR-15a-5p | −0.1049 | −0.1199 | −0.2750 | −0.9136 A*,B* |
miR-16-5p | −0.2776 | −0.1423 | −0.1535 | −1.0421 B* |
miR-17-5p | 0.0247 | −0.1487 | −0.7379 | −0.8489 A* |
miR-20a-5p | −0.1165 | −0.2951 | −0.3943 | −0.9500 |
miR-21-5p | 0.1431 | −0.1907 | −0.4275 | −0.4769 |
miR-23a-3p | −0.0880 | −0.1931 | −0.8014 | −0.3126 |
miR-26b-5p | 0.0941 | −0.8565 | −0.8884 | −0.7090 |
miR-30b-5p | −0.2360 | −0.2725 | −0.6944 | −0.7352 |
miR-92a-3p | −0.1393 | −0.2153 | −0.0081 | −0.5579 |
miR-93-5p | −0.3415 | −0.3073 | −0.2982 | −0.7645 |
miR-103a-3p | −0.5179 | −0.0470 | −0.5547 | −0.6271 |
miR-107 | −0.4478 | −0.6237 | −0.7437 | −0.5458 |
miR-125b-5p | 0.0212 | −0.5198 | −0.5544 | −0.4658 |
miR-126-3p | 0.2287 | −0.0438 | −0.8228 | −0.1455 |
miR-130a-3p | 0.5158 | 0.0752 | −0.4787 | −0.8639 |
miR-142-3p | 0.1614 | 0.5838 | −0.4787 | −0.8639 B* |
miR-143-3p | 0.0969 | −0.8183 | −1.2904 | −0.3064 |
miR-148a-3p | 0.1146 | −0.0216 | −0.2655 | −0.2943 |
miR-150-5p | −0.0463 | −0.3419 | −1.8395 | −0.3348 |
miR-152-3p | 0.3355 | 0.9672 | −1.2705 D* | −0.4368 B* |
miR-153-3p | −0.3953 | −0.1152 | −0.3229 | 0.1719 |
miR-181c-5p | 0.1744 | 0.0159 | −0.8334 | −0.0790 |
miR-185-5p | −0.0397 | 0.0226 | 0.0298 | −0.7151 |
miR-186-5p | −0.0813 | −0.2855 | −0.4653 | −0.6009 |
miR-193b-3p | 0.2956 | −0.0798 | −0.7962 | 0.4360 |
miR-193a-5p | −0.3834 | −0.2044 | 0.1922 | 0.0928 |
cmiR-199a-3p | 0.3269 | −0.2650 | −1.2600 | −0.1582 |
miR-205-5p | 0.4140 | −0.7130 | −0.1341 | −0.5216 |
miR-210-3p | 0.4585 | −0.0682 | 0.0717 | −0.5635 |
miR-221-3p | 0.2189 | −0.1704 | −0.5812 | −0.1273 |
miR-222-3p | 0.1647 | −0.1553 | −0.7543 | −0.5779 |
miR-223-3p | 0.0165 | −0.4776 | −1.1839 | −0.5409 |
miR-224-5p | −0.6883 | −0.3592 | −1.5274 | −0.6447 |
miR-326 | 0.5234 | −0.1400 | −0.4710 | −0.0317 |
miR-339-5p | 0.1477 | −0.3231 | −0.6830 | −0.4544 |
miR-342-3p | 0.0605 | −0.0595 | −1.0074 | −0.5013 |
miR-361-5p | −0.0882 | −0.2986 | −1.0626 | −0.5139 |
miR-376a-3p | −0.3842 | −0.3047 | −0.3927 | 0.6082 |
miR-423-5p | −0.0533 | −0.1089 | 0.1881 | −0.0986 |
miR-424-5p | −0.3941 | −0.3157 | −0.8417 | −0.8297 |
miR-484 | 0.0297 | 0.0716 | −0.4219 | −0.2730 |
miR-486-5p | −0.1620 | 0.1333 | 0.3238 | −0.7204 B* |
miR-505-3p | 0.0578 | 0.5247 | 0.8710 | −0.8124 B*,C* |
miR-576-5p | −0.2973 | −0.4956 | −0.3756 | −0.7959 |
miR-652-3p | −0.0238 | −0.3095 | −0.4288 | −0.2717 |
miR-744-5p | 0.4028 | −0.5303 F* | −0.6964 D* | 0.0582 |
DEmiRNA Effect via Estimated Targets in Stroke | ||
---|---|---|
General biological effect | Potential positive effect of targets on stroke-cell survival | Potential negative effect of targets on stroke-cell death |
Neurogenesis, neurite outgrowth, neuronal re-networking, synaptic plasticity | CAPZA2 [30], KIF23 [31], ACTR2 [32], SHOC2 [33], FZD9 [34], CRIM1 [35,36], LAMC1 [37], SKI [38], EIFG2 [39] | |
Oxidative stress response | YTHDC1 79, EIF2B2 80, BZW1 83, MCL1 138 | SIK1 [40] |
Autophagy | HSPA8 [41,42], ATG14 [43] | |
Neurite/synapse rejuvenation | ARHGAP12 [44] | |
Acute/delayed cell death, apoptosis regulation | MCL1 [45], | RAB3IP [46], ABL2 [47,48], MAP2K3 [49], CCDN1 [50], ZMAT3 [51], PMAIP1 [52], PTEN [53] |
Tissue ions and nucleotide homoeostasis | SLC28A1 [54] | WNK3 [55] |
Translation regulation | AGO4 [56] | |
Protein synthesis | RBM12B [57] | RPL14 [58] |
Angiogenesis | VEGFR2 [59], SPRED1 [60] | |
Platelets aggregation | CRKL [61], ITGA2 [62,63] | |
Protein aggregation—dementia | APP [64,65], SMAD7 [66], DNAJC [67,68], | |
Neuroinflammation | BTG2 [69] 142 | SOC5 [70], BTN3A3 [71], RFK [72,73], TXNIP [74,75], PTEN [76] |
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Gendosz de Carrillo, D.; Kocikowska, O.; Krzan, A.; Student, S.; Rak, M.; Nowak-Andraka, M.; Mi, J.; Burek, M.; Lasek-Bal, A.; Jędrzejowska-Szypułka, H. Reduced Expression of Selected Exosomal MicroRNAs Is Associated with Poor Outcomes in Patients with Acute Stroke Receiving Reperfusion Therapy—Preliminary Study. Int. J. Mol. Sci. 2025, 26, 9533. https://doi.org/10.3390/ijms26199533
Gendosz de Carrillo D, Kocikowska O, Krzan A, Student S, Rak M, Nowak-Andraka M, Mi J, Burek M, Lasek-Bal A, Jędrzejowska-Szypułka H. Reduced Expression of Selected Exosomal MicroRNAs Is Associated with Poor Outcomes in Patients with Acute Stroke Receiving Reperfusion Therapy—Preliminary Study. International Journal of Molecular Sciences. 2025; 26(19):9533. https://doi.org/10.3390/ijms26199533
Chicago/Turabian StyleGendosz de Carrillo, Daria, Olga Kocikowska, Aleksandra Krzan, Sebastian Student, Małgorzata Rak, Magdalena Nowak-Andraka, Junqiao Mi, Małgorzata Burek, Anetta Lasek-Bal, and Halina Jędrzejowska-Szypułka. 2025. "Reduced Expression of Selected Exosomal MicroRNAs Is Associated with Poor Outcomes in Patients with Acute Stroke Receiving Reperfusion Therapy—Preliminary Study" International Journal of Molecular Sciences 26, no. 19: 9533. https://doi.org/10.3390/ijms26199533
APA StyleGendosz de Carrillo, D., Kocikowska, O., Krzan, A., Student, S., Rak, M., Nowak-Andraka, M., Mi, J., Burek, M., Lasek-Bal, A., & Jędrzejowska-Szypułka, H. (2025). Reduced Expression of Selected Exosomal MicroRNAs Is Associated with Poor Outcomes in Patients with Acute Stroke Receiving Reperfusion Therapy—Preliminary Study. International Journal of Molecular Sciences, 26(19), 9533. https://doi.org/10.3390/ijms26199533