Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS)
Abstract
:1. Introduction
2. Results
2.1. Clinical Characteristics
2.2. Small Extracellular Vesicles (sEVs) in Patients with PAPS and aPL
2.3. sEVs from aPL and PAPS Patients Produce Endothelial Dysfunction
2.4. PAPS sEVs Produced Monocyte Activation
2.5. Differential Expression Profiles of sEV-Derived miRNA between PAPS and aPL Patients
2.6. sEV-Derived miRNAs Produce HUVEC Cell Activation via PTEN Pathway and Monocyte Activation via NOTCH1
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Sample Collection
4.3. Anti-Phospholipid Antibody Detection
4.4. Small RNA-Sequencing of sEV-miRNAs
4.5. Cell Cultures
4.6. RNA Extraction and RT-qPCR Gene Expression
4.7. Apoptosis and Proliferation Assay
4.8. Luciferase Assay
4.9. Immunofluorescence on Primary Cells
4.10. Measurement of Cytokines Levels by Enzyme-Linked Immunosorbent Assay (ELISA)
4.11. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Characteristic | PAPS (n = 50) | aPL (n = 30) | HD (n = 30) | p Value ‡ |
---|---|---|---|---|
Female sex, n (%) | 30 (60.0) | 20 (66.6) | 20 (66.6) | 0.637 |
Median age (IQR), y | 51 (44–60) | 54 (44–60) | 49 (40–59) | 0.198 |
Median duration of APS (IQR), y | 9.4 (3–14) | 9.9 (4–12) | na | 0.597 |
PAPS clinical criteria for initial anticoagulation, n (%) | ||||
Venous thrombosis | 37 (74.0) | 0 (0) | 0 (0) | <0.001 |
Arterial thrombosis | 25 (50.0) | 0 (0) | 0 (0) | <0.001 |
Both arterial and venous | 12 (24.0) | 0 (0) | 0 (0) | <0.001 |
Obstetrical medical history, n (%) | 11 (22.0) | 0 (0) | 0 (0) | <0.001 |
Other non-thrombotic manifestations, n (%) | ||||
Valvular heart disease * | 19 (38.0) | 2 (6.7) | 0 (0) | 0.002 |
Renal thrombotic microangiopathy | 9 (18.0) | 1 (3.3) | 0 (0) | 0.081 |
Livedo reticularis | 23 (46.0) | 1 (3.3) | 0 (0) | <0.001 |
Migraine | 23 (46.0) | 4 (13.3) | 0 (0) | 0.003 |
Thrombocytopenia | 13 (26.0) | 5 (16.7) | 0 (0) | 0.414 |
Laboratory profile at inclusion, n (%) | ||||
Lupus anticoagulant | 50 (100) | 30 (100) | nd | 1.000 |
Lupus anticoagulant alone | 7 (14.0) | 3 (10.0) | nd | 0.736 |
IgG/IgM antibodies | ||||
aCL | 44 (88.0) | 24 (80.0) | nd | 0.351 |
Anti-β2GPI | 41 (82.0) | 23 (76.7) | nd | 0.577 |
Anti-aPS/PT | 15 (30.0) | 10 (33.3) | nd | 0.806 |
IgG aCL, GPL units | 153.5 (152.8) | 141.0 (162.7) | nd | 0.671 |
IgM aCL, MPL units | 26.9 (53.3) | 16.5 (20.3) | nd | 0.309 |
IgG anti-β2GPI, GPL units | 162.3 (217.4) | 190.15 (241.0) | nd | 0.596 |
IgM anti-β2GPI, MPL units | 37.5 (73.3) | 25.5 (47.6) | nd | 0.426 |
Lupus anticoagulant and IgG aCL and IgG anti-β2GPI antibodies, n (%) | 41 (82%) | 25 (83.3) | nd | 1.000 |
GAPSS risk for thrombosis † | ||||
Mean score (SD) | 15.1 (2.1) | 14.2 (2.7) | na | 0.133 |
Score, n (%) | ||||
<10 | 1 (2.0) | 1 (3.3) | na | 1.000 |
10 to <15 | 32 (64.0) | 13 (43.3) | na | 0.103 |
≥15 | 17 (34.0) | 16 (53.3) | na | 0.105 |
Aspirin use, n (%) | 10 (20.0) | 25 (83.3) | 0 (0) | <0.001 |
Antimalarial or immunosuppressive therapy | 0 (0) | 0 (0) | 0 (0) | 1.000 |
Vitamin K antagonist therapy, n (%) | 50 (100) | 0 (0) | 0 (0) | <0.001 |
Coexisting cardiovascular risk factors, n (%) | ||||
Smoking | 20 (40.0) | 10 (33.3) | 12 (40.0) | 0.637 |
Dyslipedemia | 23 (46.0) | 11 (36.7) | 5 (16.7) | 0.487 |
Diabetes mellitus | 8 (16.0) | 3 (10.0) | 0 (0) | 0.522 |
Hypertension | 21 (42.0) | 10 (33.3) | 0 (0) | 0.485 |
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Solé, C.; Royo, M.; Sandoval, S.; Moliné, T.; Cortés-Hernández, J. Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS). Int. J. Mol. Sci. 2023, 24, 11607. https://doi.org/10.3390/ijms241411607
Solé C, Royo M, Sandoval S, Moliné T, Cortés-Hernández J. Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS). International Journal of Molecular Sciences. 2023; 24(14):11607. https://doi.org/10.3390/ijms241411607
Chicago/Turabian StyleSolé, Cristina, Maria Royo, Sebastian Sandoval, Teresa Moliné, and Josefina Cortés-Hernández. 2023. "Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS)" International Journal of Molecular Sciences 24, no. 14: 11607. https://doi.org/10.3390/ijms241411607