https://orcid.org/0000-0002-2857-1986
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Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs, able to regulate cellular functions by induction of mRNA degradation and post-transcriptional repression of gene expression. Platelets are the major source of circulating miRNAs, with significant regulatory potential on cardiovascular pathophysiology and other diseases. MiRNAs have been shown to modify the expression of platelet proteins, which influence the platelets reactivity. Circulating miRNAs can be determined from plasma, serum, or whole blood, and they can be used as diagnostic and prognostic biomarkers as well as therapeutic targets including cardiovascular diseases (CVDs). Herein, we present original results from bioinformatic analyses, which identified top 22 platelet-related miRNAs including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p as widely involved in platelet reactivity and associated diseases, including CVDs, Alzheimer’s and cerebrovascular diseases, cancer and hypertension. Analysis focused on the identification of the highly regulatory targets shared between those miRNAs identified 43 of them. Best ranked genes associated with overall platelet activity and most susceptible for noncoding regulation were PTEN, PIK3R1, CREB1, APP, and MAPK1. Top targets also strongly associated with CVDs were VEGFA, IGF1, ESR1, BDNF, and PPARG. Top targets associated with other platelet-related diseases including cancer identified in our study were TP53, KRAS, and CCND1. The most affected pathways by top miRNAs and top targets included diseases of signal transduction by Growth Factor Receptors (GDFRs) and second messengers, platelet activation, signaling, and aggregation, signaling by VEGF, MAPK family signaling cascades, and signaling by Interleukins. Terms specific only for platelet-related miRNAs included coronary artery disease, platelet degranulation, and neutrophil degranulation, while for the top platelet-related genes it was Estrogen Signaling Receptor (ESR) mediated signaling, extra-nuclear estrogen signaling, and endometriosis. Our results show the novel features of platelet physiology and may provide a basis for further clinical studies focused on platelet reactivity. They also show in which aspects miRNAs can be promising biomarkers of platelet-related pathological processes.
Highlights of the article
By using in silico analysis, we identified 22 miRNAs which are potential biomarkers of platelet function, including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p.
Top miRNAs involved in platelet reactivity showed significant overrepresentation of platelet-related targets involved in Alzheimer’s and cerebrovascular diseases, cancer, and hypertension.
We found that the most often targeted genes by the top miRNAs were related to platelet activity (PTEN, PIK3R1, CREB1, APP, and MAPK1), CVDs, and platelet-related diseases (VEGFA, IGF1, ESR1, BDNF, PPARG).
Top targets associated with other platelet-related diseases including cancer identified in our study were i.a TP53, KRAS, and CCND1.
The most affected platelet-related pathways included signaling by interleukins, diseases associated with GFRs, MAPK family cascades signaling, and platelet activation and aggregation.
Top platelet-related targets, but not miRNAs, showed significant association with ESR mediated pathways and endometriosis.
Acknowledgements
This paper was written as a part of the cooperation of the international scientific group I-COMET (International Cardiovascular and Cardiometabolic Research Team- www.icomet.science).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Contributors
ZW, CE, PC DJ, and MP contributed to the data collection and elaboration, writing, and approval of the manuscript; and is the guarantor of the article. ZW contributed to the bioinformatic analysis and interpretation of data. ZW contributed to the visualization of the data. DVL, MW, AF, HS, and AS contributed writing, editing, discussion, and approval of the manuscript. JSM contributed to supervising, revising, and approval the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
