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Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19
Jessica Gambardella1, Urna Kansakar1, Celestino Sardu1
1Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.).
Insights
Exosomes carrying miR-145 and miR-885 are implicated in COVID-19 blood clot formation. These microRNAs play a key role in the pathogenesis of thromboembolic complications, potentially impacting Long COVID.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Thromboembolic complications are a significant concern in Coronavirus Disease 2019 (COVID-19).
- Exosomal microRNAs are increasingly recognized for their roles in disease pathogenesis.
- The specific mechanisms linking COVID-19 to clotting disorders require further elucidation.
Purpose of the Study:
- To investigate the role of exosomal microRNAs in the development of thromboembolic complications in COVID-19 patients.
- To identify specific microRNAs associated with disease severity markers like D-dimer.
- To explore the functional impact of these microRNAs on endothelial cell function.
Main Methods:
- Isolation of circulating exosomes from COVID-19 patients.
- Correlation analysis of exosomal microRNA levels (miR-145, miR-885) with D-dimer levels.
- In vitro studies using human endothelial cells treated with COVID-19 patient serum.
Main Results:
- Exosomal miR-145 and miR-885 levels significantly correlated with D-dimer levels in COVID-19 patients.
- Human endothelial cells express key SARS-CoV-2 entry cofactors.
- COVID-19 serum treatment reduced exosomal miR-145/miR-885 release, increased endothelial cell apoptosis, and impaired angiogenesis.
Conclusions:
- Exosomal miR-145 and miR-885 are functionally involved in modulating thromboembolic events in COVID-19.
- These microRNAs may represent novel therapeutic targets for managing COVID-19-associated clotting disorders.
- Findings have implications for understanding systemic manifestations of COVID-19, including Long COVID.
Abstract:
We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.
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