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Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke.
Int J Mol Sci. 2022 Apr 20; 23(9)IJ

Abstract

BACKGROUND

Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic mediators, including microRNAs (miRNAs) and extracellular vesicles (EVs). In the current study we aimed to assess circulating miRNAs profile related to platelet function and inflammation and circulating EVs from platelets, leukocytes, and endothelial cells to analyse their diagnostic and predictive utility in patients with acute IS.

METHODS

The study population consisted of 28 patients with the diagnosis of the acute IS. The control group consisted of 35 age- and gender-matched patients on acetylsalicylic acid (ASA) therapy without history of stroke and/or TIA with established stable coronary artery disease (CAD) and concomitant cardiovascular risk factors. Venous blood samples were collected from the control group and patients with IS on ASA therapy (a) 24 h after onset of acute IS, (b) 7-days following index hospitalization. Flow cytometry was used to determine the concentration of circulating EVs subtypes (from platelets, leukocytes, and endothelial cells) in platelet-depleted plasma and qRT-PCR was used to determine several circulating plasma miRNAs (miR-19a-3p, miR-186-5p and let-7f).

RESULTS

Patients with high platelet reactivity (HPR, based on arachidonic acid-induced platelet aggregometry) had significantly elevated platelet-EVs (CD62+) and leukocyte-EVs (CD45+) concentration compared to patients with normal platelet reactivity at the day of 1 acute-stroke (p = 0.012, p = 0.002, respectively). Diagnostic values of baseline miRNAs and EVs were evaluated with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for miR-19a-3p was 0.755 (95% CI, 0.63-0.88) p = 0.004, for let-7f, it was 0.874 (95% CI, 0.76-0.99) p = 0.0001; platelet-EVs was 0.776 (95% CI, 0.65-0.90) p = 0.001, whereas for leukocyte-EVs, it was 0.715 (95% CI, 0.57-0.87) p = 0.008. ROC curve showed that pooling the miR-19a-3p expressions, platelet-EVs, and leukocyte-EVs concentration yielded a higher AUC than the value of each individual biomarker as AUC was 0.893 (95% CI, 0.79-0.99). Patients with moderate stroke had significantly elevated miR-19a-3p expression levels compared to patients with minor stroke at the first day of IS. (AUC: 0.867, (95% CI, 0.74-0.10) p = 0.001).

CONCLUSION

Combining different biomarkers of processes underlying IS pathophysiology might be beneficial for early diagnosis of ischemic events. Thus, we believe that in the future circulating biomarkers might be used in the prehospital phase of IS. In particular, circulating plasma EVs and non-coding RNAs including miRNAs are interesting candidates as bearers of circulating biomarkers due to their high stability in the blood and making them highly relevant biomarkers for IS diagnostics.

Links

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Authors+Show Affiliations

Eyileten C
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B Str., 02-097 Warsaw, Poland. Genomics Core Facility, Center of New Technologies (CeNT), University of Warsaw, 02-097 Warsaw, Poland.
Jakubik D
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B Str., 02-097 Warsaw, Poland.
Shahzadi A
Department of Medical Pharmacology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul 34096, Turkey.
Gasecka A
Department of Cardiology, Medical University of Warsaw, 02-091 Warsaw, Poland.
van der Pol E
Biomedical Engineering & Physics, Amsterdam UMC, University of Amsterdam, 1012 Amsterdam, The Netherlands. Vesicle Observation Centre, Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, University of Amsterdam, 1012 Amsterdam, The Netherlands.
De Rosa S
Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy.
Siwik D
Department of Cardiology, Medical University of Warsaw, 02-091 Warsaw, Poland.
Gajewska M
Department of Cardiology, Medical University of Warsaw, 02-091 Warsaw, Poland.
Mirowska-Guzel D
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B Str., 02-097 Warsaw, Poland.
Kurkowska-Jastrzebska I
2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland.
Czlonkowska A
2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland.
Postula M
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B Str., 02-097 Warsaw, Poland.

MeSH

BiomarkersCirculating MicroRNAEndothelial CellsExtracellular VesiclesHumansInflammationIschemic StrokeMicroRNAsROC CurveStroke

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35562921

Citation

Eyileten, Ceren, et al. "Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke." International Journal of Molecular Sciences, vol. 23, no. 9, 2022.
Eyileten C, Jakubik D, Shahzadi A, et al. Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke. Int J Mol Sci. 2022;23(9).
Eyileten, C., Jakubik, D., Shahzadi, A., Gasecka, A., van der Pol, E., De Rosa, S., Siwik, D., Gajewska, M., Mirowska-Guzel, D., Kurkowska-Jastrzebska, I., Czlonkowska, A., & Postula, M. (2022). Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke. International Journal of Molecular Sciences, 23(9). https://doi.org/10.3390/ijms23094530
Eyileten C, et al. Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke. Int J Mol Sci. 2022 Apr 20;23(9) PubMed PMID: 35562921.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke. AU - Eyileten,Ceren, AU - Jakubik,Daniel, AU - Shahzadi,Andleeb, AU - Gasecka,Aleksandra, AU - van der Pol,Edwin, AU - De Rosa,Salvatore, AU - Siwik,Dominika, AU - Gajewska,Magdalena, AU - Mirowska-Guzel,Dagmara, AU - Kurkowska-Jastrzebska,Iwona, AU - Czlonkowska,Anna, AU - Postula,Marek, Y1 - 2022/04/20/ PY - 2022/02/13/received PY - 2022/04/04/revised PY - 2022/04/14/accepted PY - 2022/5/14/entrez PY - 2022/5/15/pubmed PY - 2022/5/18/medline KW - EVs KW - ischemia KW - let-7f KW - leukocyte extracellular vesicles KW - miR-186 KW - miR-19a KW - platelet extracellular vesicles KW - platelet reactivity KW - prognosis KW - stroke severity JF - International journal of molecular sciences JO - Int J Mol Sci VL - 23 IS - 9 N2 - BACKGROUND: Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic mediators, including microRNAs (miRNAs) and extracellular vesicles (EVs). In the current study we aimed to assess circulating miRNAs profile related to platelet function and inflammation and circulating EVs from platelets, leukocytes, and endothelial cells to analyse their diagnostic and predictive utility in patients with acute IS. METHODS: The study population consisted of 28 patients with the diagnosis of the acute IS. The control group consisted of 35 age- and gender-matched patients on acetylsalicylic acid (ASA) therapy without history of stroke and/or TIA with established stable coronary artery disease (CAD) and concomitant cardiovascular risk factors. Venous blood samples were collected from the control group and patients with IS on ASA therapy (a) 24 h after onset of acute IS, (b) 7-days following index hospitalization. Flow cytometry was used to determine the concentration of circulating EVs subtypes (from platelets, leukocytes, and endothelial cells) in platelet-depleted plasma and qRT-PCR was used to determine several circulating plasma miRNAs (miR-19a-3p, miR-186-5p and let-7f). RESULTS: Patients with high platelet reactivity (HPR, based on arachidonic acid-induced platelet aggregometry) had significantly elevated platelet-EVs (CD62+) and leukocyte-EVs (CD45+) concentration compared to patients with normal platelet reactivity at the day of 1 acute-stroke (p = 0.012, p = 0.002, respectively). Diagnostic values of baseline miRNAs and EVs were evaluated with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for miR-19a-3p was 0.755 (95% CI, 0.63-0.88) p = 0.004, for let-7f, it was 0.874 (95% CI, 0.76-0.99) p = 0.0001; platelet-EVs was 0.776 (95% CI, 0.65-0.90) p = 0.001, whereas for leukocyte-EVs, it was 0.715 (95% CI, 0.57-0.87) p = 0.008. ROC curve showed that pooling the miR-19a-3p expressions, platelet-EVs, and leukocyte-EVs concentration yielded a higher AUC than the value of each individual biomarker as AUC was 0.893 (95% CI, 0.79-0.99). Patients with moderate stroke had significantly elevated miR-19a-3p expression levels compared to patients with minor stroke at the first day of IS. (AUC: 0.867, (95% CI, 0.74-0.10) p = 0.001). CONCLUSION: Combining different biomarkers of processes underlying IS pathophysiology might be beneficial for early diagnosis of ischemic events. Thus, we believe that in the future circulating biomarkers might be used in the prehospital phase of IS. In particular, circulating plasma EVs and non-coding RNAs including miRNAs are interesting candidates as bearers of circulating biomarkers due to their high stability in the blood and making them highly relevant biomarkers for IS diagnostics. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/35562921/Diagnostic_Performance_of_Circulating_miRNAs_and_Extracellular_Vesicles_in_Acute_Ischemic_Stroke_ DB - PRIME DP - Unbound Medicine ER -