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MicroRNAs as Biomarkers and Effector Molecules of Thrombosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2020) | Viewed by 41490

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Dr. Constantino Martínez

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Servicio de Hematología y Oncología Médica, Hospital General Universitario Morales Meseguer, Centro Regional de Hemodonación, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
Interests: miRNAs; inflammation; thrombosis; biomarkers; animal models; cellular models

Dr. Rocio Gonzalez-Conejero

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University of Murcia. Centro Regional de Hemodonación, IMIB-Arrixaca, Murcia, Spain

Special Issue Information

Dear Colleagues,

This Special Issue will cover the role of microRNAs in diseases related with thrombosis. miRNAs were discovered almost 30 years ago and are now established as important molecules implicated in gene regulation. They are implicated in almost all physiological processes, and their dysregulation may provoke many pathological outcomes, cancer and cardiovascular diseases being the most studied. This Special Issue intends to bring together two important aspects of miRNA biology, their role as regulators of processes implicated in the development of thrombotic episodes and their role as markers of arterial and venous thrombosis. Given the variability between individuals and technical issues, there is still work to do concerning the standardization of the use of miRNAs as plasma biomarkers. Despite this, their use as potential diagnostic and prognostic tools is of high interest.

We thus invite established and young investigators to share their research by sending original and review articles that will allow advancing in the search of miRNAs that may serve as new biomarkers as well as new mechanisms implicated in the pathophysiology of thrombosis.

Dr. Rocio Gonzalez-Conejero
Dr. Constantino Martínez
Guest Editors

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Keywords

miRNAs
thrombosis
plasma biomarkers
genetic biomarkers
cancer
cardiovascular diseases
platelets
therapeutics

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Published Papers (9 papers)

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Research

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13 pages, 1453 KiB

Open AccessArticle

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y₁₂ Inhibition

by Aitana Braza-Boïls, Temo Barwari, Clemens Gutmann, Mark R. Thomas, Heather M. Judge, Abhishek Joshi, Raimund Pechlaner, Manu Shankar-Hari, Ramzi A. Ajjan, Ian Sabroe, Robert F. Storey and Manuel Mayr

Int. J. Mol. Sci. 2020, 21(8), 2897; https://doi.org/10.3390/ijms21082897 - 21 Apr 2020

Cited by 17 | Viewed by 3883

Abstract

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y₁₂ inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y₁₂ inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y₁₂ inhibition. While P2Y₁₂ inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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22 pages, 3410 KiB

Open AccessArticle

Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation Status in Sepsis

by Bernadett Szilágyi, Zsolt Fejes, Szilárd Póliska, Marianna Pócsi, Zsolt Czimmerer, Andreas Patsalos, Ferenc Fenyvesi, Ágnes Rusznyák, György Nagy, György Kerekes, Mariann Berhés, Ildikó Szűcs, Satya P. Kunapuli, János Kappelmayer and Béla Nagy, Jr.

Int. J. Mol. Sci. 2020, 21(3), 866; https://doi.org/10.3390/ijms21030866 - 29 Jan 2020

Cited by 32 | Viewed by 4353

Abstract

In sepsis, platelets may become activated via toll-like receptors (TLRs), causing microvascular thrombosis. Megakaryocytes (MKs) also express these receptors; thus, severe infection may modulate thrombopoiesis. To explore the relevance of altered miRNAs in platelet activation upon sepsis, we first investigated sepsis-induced miRNA expression in platelets of septic patients. The effect of abnormal Dicer level on miRNA expression was also evaluated. miRNAs were profiled in septic vs. normal platelets using TaqMan Open Array. We validated platelet miR-26b with its target SELP (P-selectin) mRNA levels and correlated them with clinical outcomes. The impact of sepsis on MK transcriptome was analyzed in MEG-01 cells after lipopolysaccharide (LPS) treatment by RNA-seq. Sepsis-reduced miR-26b was further studied using Dicer1 siRNA and calpain inhibition in MEG-01 cells. Out of 390 platelet miRNAs detected, there were 121 significantly decreased, and 61 upregulated in sepsis vs. controls. Septic platelets showed attenuated miR-26b, which were associated with disease severity and mortality. SELP mRNA level was elevated in sepsis, especially in platelets with increased mean platelet volume, causing higher P-selectin expression. Downregulation of Dicer1 generated lower miR-26b with higher SELP mRNA, while calpeptin restored miR-26b in MEG-01 cells. In conclusion, decreased miR-26b in MKs and platelets contributes to an increased level of platelet activation status in sepsis. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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17 pages, 751 KiB

Open AccessArticle

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma

by Julia Oto, Silvia Navarro, Anders C. Larsen, María José Solmoirago, Emma Plana, David Hervás, Álvaro Fernández-Pardo, Francisco España, Søren R. Kristensen, Ole Thorlacius-Ussing and Pilar Medina

Int. J. Mol. Sci. 2020, 21(3), 840; https://doi.org/10.3390/ijms21030840 - 28 Jan 2020

Cited by 34 | Viewed by 3776

Abstract

Cancer-associated venous thrombosis (VTE) increases mortality and morbidity. However, limited tools are available to identify high risk patients. Upon activation, neutrophils release their content through different mechanisms, thereby prompting thrombosis. We explored plasma microRNAs (miRNAs) and neutrophil activation markers to predict VTE in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC). Twenty-six PDAC and 6 DECC patients recruited at cancer diagnosis, were examined for deep vein thrombosis and pulmonary embolisms, and were then followed-up with clinical examinations, blood collections, and biCUS. Ten patients developed VTE and were compared with 22 age- and sex-matched controls. miRNA expression levels were measured at diagnosis and right before VTE, and neutrophil activation markers (cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase) were measured in every sample obtained during follow-up. We obtained a profile of 7 miRNAs able to estimate the risk of future VTE at diagnosis (AUC = 0.95; 95% Confidence Interval (CI) (0.987, 1)) with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. Seven miRNAs were up- or down-regulated before VTE compared with diagnosis. We obtained a predictive model of VTE with calprotectin as predictor (AUC = 0.77; 95% CI (0.57, 0.95)). This is the first study that addresses the ability of plasma miRNAs and neutrophil activation markers to predict VTE in PDAC and DECC. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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Review

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14 pages, 1322 KiB

Open AccessReview

MicroRNAs as New Regulators of Neutrophil Extracellular Trap Formation

by Sonia Águila, Ascensión M. de los Reyes-García, María P. Fernández-Pérez, Laura Reguilón-Gallego, Laura Zapata-Martínez, Inmaculada Ruiz-Lorente, Vicente Vicente, Rocío González-Conejero and Constantino Martínez

Int. J. Mol. Sci. 2021, 22(4), 2116; https://doi.org/10.3390/ijms22042116 - 20 Feb 2021

Cited by 20 | Viewed by 5132

Abstract

Neutrophil extracellular traps (NETs) are formed after neutrophils expelled their chromatin content in order to primarily capture and eliminate pathogens. However, given their characteristics due in part to DNA and different granular proteins, NETs may induce a procoagulant response linking inflammation and thrombosis. Unraveling NET formation molecular mechanisms as well as the intracellular elements that regulate them is relevant not only for basic knowledge but also to design diagnostic and therapeutic tools that may prevent their deleterious effects observed in several inflammatory pathologies (e.g., cardiovascular and autoimmune diseases, cancer). Among the potential elements involved in NET formation, several studies have investigated the role of microRNAs (miRNAs) as important regulators of this process. miRNAs are small non-coding RNAs that have been involved in the control of almost all physiological processes in animals and plants and that are associated with the development of several pathologies. In this review, we give an overview of the actual knowledge on NETs and their implication in pathology with a special focus in cardiovascular diseases. We also give a brief overview on miRNA biology to later focus on the different miRNAs implicated in NET formation and the perspectives opened by the presented data. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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21 pages, 943 KiB

Open AccessReview

Role of microRNAs in Hemophilia and Thrombosis in Humans

by Katarzyna I. Jankowska, Zuben E. Sauna and Chintamani D. Atreya

Int. J. Mol. Sci. 2020, 21(10), 3598; https://doi.org/10.3390/ijms21103598 - 20 May 2020

Cited by 27 | Viewed by 4231

Abstract

MicroRNAs (miRNA) play an important role in gene expression at the posttranscriptional level by targeting the untranslated regions of messenger RNA (mRNAs). These small RNAs have been shown to control cellular physiological processes including cell differentiation and proliferation. Dysregulation of miRNAs have been associated with numerous diseases. In the past few years miRNAs have emerged as potential biopharmaceuticals and the first miRNA-based therapies have entered clinical trials. Our recent studies suggest that miRNAs may also play an important role in the pathology of genetic diseases that are currently considered to be solely due to mutations in the coding sequence. For instance, among hemophilia A patients there exist a small subset, with normal wildtype genes; i.e., lacking in mutations in the coding and non-coding regions of the F8 gene. Similarly, in many patients with missense mutations in the F8 gene, the genetic defect does not fully explain the severity of the disease. Dysregulation of miRNAs that target mRNAs encoding coagulation factors have been shown to disturb gene expression. Alterations in protein levels involved in the coagulation cascade mediated by miRNAs could lead to bleeding disorders or thrombosis. This review summarizes current knowledge on the role of miRNAs in hemophilia and thrombosis. Recognizing and understanding the functions of miRNAs by identifying their targets is important in identifying their roles in health and diseases. Successful basic research may result in the development and improvement of tools for diagnosis, risk evaluation or even new treatment strategies. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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23 pages, 1046 KiB

Open AccessReview

microRNAs as Promising Biomarkers of Platelet Activity in Antiplatelet Therapy Monitoring

by Teresa L. Krammer, Manuel Mayr and Matthias Hackl

Int. J. Mol. Sci. 2020, 21(10), 3477; https://doi.org/10.3390/ijms21103477 - 14 May 2020

Cited by 40 | Viewed by 4105

Abstract

Given the high morbidity and mortality of cardiovascular diseases (CVDs), novel biomarkers for platelet reactivity are urgently needed. Ischemic events in CVDs are causally linked to platelets, small anucleate cells important for hemostasis. The major side-effect of antiplatelet therapy are life-threatening bleeding events. Current platelet function tests are not sufficient in guiding treatment decisions. Platelets host a broad spectrum of microRNAs (miRNAs) and are a major source of cell-free miRNAs in the blood stream. Platelet-related miRNAs have been suggested as biomarkers of platelet activation and assessment of antiplatelet therapy responsiveness. Platelets release miRNAs upon activation, possibly leading to alterations of plasma miRNA levels in conjunction with CVD or inadequate platelet inhibition. Unlike current platelet function tests, which measure platelet activation ex vivo, signatures of platelet-related miRNAs potentially enable the assessment of in vivo platelet reactivity. Evidence suggests that some miRNAs are responsive to platelet inhibition, making them promising biomarker candidates. In this review, we explain the secretion of miRNAs upon platelet activation and discuss the potential use of platelet-related miRNAs as biomarkers for CVD and antiplatelet therapy monitoring, but also highlight remaining gaps in our knowledge and uncertainties regarding clinical utility. We also elaborate on technical issues and limitations concerning plasma miRNA quantification. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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14 pages, 472 KiB

Open AccessReview

Role of microRNAs in Venous Thromboembolism

by Vânia M. Morelli, Sigrid K. Brækkan and John-Bjarne Hansen

Int. J. Mol. Sci. 2020, 21(7), 2602; https://doi.org/10.3390/ijms21072602 - 9 Apr 2020

Cited by 29 | Viewed by 4207

Abstract

MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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20 pages, 793 KiB

Open AccessReview

MicroRNA (miRNA): A New Dimension in the Pathogenesis of Antiphospholipid Syndrome (APS)

by Przemysław J. Kotyla and Md Asiful Islam

Int. J. Mol. Sci. 2020, 21(6), 2076; https://doi.org/10.3390/ijms21062076 - 18 Mar 2020

Cited by 9 | Viewed by 5604

Abstract

MicroRNAs (miRNAs) are single-stranded, endogenous RNA molecules that play a significant role in the regulation of gene expression as well as cell development, differentiation, and function. Recent data suggest that these small molecules are responsible for the regulation of immune responses. Therefore, they may act as potent modulators of the immune system and play an important role in the development of several autoimmune diseases. Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by venous and/or arterial thromboses and/or recurrent fetal losses in the presence of antiphospholipid antibodies (aPLs). Several lines of evidence suggest that like other autoimmune disorders, miRNAs are deeply involved in the pathogenesis of APS, interacting with the function of innate and adaptive immune responses. In this review, we characterize miRNAs in the light of having a functional role in the immune system and autoimmune responses focusing on APS. In addition, we also discuss miRNAs as potential biomarkers and target molecules in treating APS. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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30 pages, 2399 KiB

Open AccessReview

Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

by Chary Lopez-Pedrera, Nuria Barbarroja, Alejandra Mª Patiño-Trives, Maria Luque-Tévar, Carmen Torres-Granados, Mª Angeles Aguirre-Zamorano, Eduardo Collantes-Estevez and Carlos Pérez-Sánchez

Int. J. Mol. Sci. 2020, 21(6), 2012; https://doi.org/10.3390/ijms21062012 - 16 Mar 2020

Cited by 23 | Viewed by 5737

Abstract

Rheumatoid Arthritis (RA), Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are the systemic autoimmune diseases (SADs) most associated with an increased risk of developing cardiovascular (CV) events. Cardiovascular disease (CVD) in SADs results from a complex interaction between traditional CV-risk factors, immune deregulation and disease activity. Oxidative stress, dyslipidemia, endothelial dysfunction, inflammatory/prothrombotic mediators (cytokines/chemokines, adipokines, proteases, adhesion-receptors, NETosis-derived-products, and intracellular-signaling molecules) have been implicated in these vascular pathologies. Genetic and genomic analyses further allowed the identification of signatures explaining the pro-atherothrombotic profiles in RA, SLE and APS. However, gene modulation has left significant gaps in our understanding of CV co-morbidities in SADs. MicroRNAs (miRNAs) are emerging as key post-transcriptional regulators of a suite of signaling pathways and pathophysiological effects. Abnormalities in high number of miRNA and their associated functions have been described in several SADs, suggesting their involvement in the development of atherosclerosis and thrombosis in the setting of RA, SLE and APS. This review focusses on recent insights into the potential role of miRNAs both, as clinical biomarkers of atherosclerosis and thrombosis in SADs, and as therapeutic targets in the regulation of the most influential processes that govern those disorders, highlighting the potential diagnostic and therapeutic properties of miRNAs in the management of CVD. Full article

(This article belongs to the Special Issue MicroRNAs as Biomarkers and Effector Molecules of Thrombosis)

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