MicroRNA Biomarkers and Platelet Reactivity

Sunderland, Nicholas; Skroblin, Philipp; Barwari, Temo; Huntley, Rachael P.; Lu, Ruifang; Joshi, Abhishek; Lovering, Ruth C.; Mayr, Manuel

doi:10.1161/circresaha.116.309303

Cited by 162 publications

(186 citation statements)

References 108 publications

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“…The latter could be mediated directly by the physical properties of platelets and platelet microparticles binding to LECs, through the release of VEGF-C upon platelet activation, 73 or via the transduction of intracellular signals mediated by noncoding microRNAs. 74 Among the signaling pathways that would be relevant figures VEGFR-3, one of the main receptors of VEGF-C. 75 The increase in VEGFR-3 levels that we observe in apoA-I treated cells reinforces the hypothesis that apoA-I might also act directly on LEC to disrupt lipid rafts and therefore modulate specific cell-signaling pathways. As binding of VEGF-C to VEGFR-3 has been reported to alter the intrinsic and phasic pumping of collecting lymphatics in rat mesentery, 76 our results reveal that apoA-I could promote lymphatic integrity through the upregulation of VEGFR-3 activity.…”

Section: Discussionsupporting

confidence: 60%

“…Afterward, platelets or platelet microparticles could adhere more efficiently to the lymphatic endothelium, thus promoting lymphatic endothelial cells integrity. The latter could be mediated directly by the physical properties of platelets and platelet microparticles binding to LECs, through the release of VEGF‐C upon platelet activation,73 or via the transduction of intracellular signals mediated by noncoding microRNAs 74. Among the signaling pathways that would be relevant figures VEGFR‐3, one of the main receptors of VEGF‐C 75…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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BackgroundSubcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.Methods and ResultsAtherosclerotic Ldlr −/− mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr −/− mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated Ldlr −/− mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.ConclusionsAltogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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“…In contrast to our results, studies using platelet-rich or platelet-poor plasma from patients with acute coronary syndrome found miR-223 levels to be decreased in patients with a very low response to P2Y 12 inhibitors, compared with normal responders [30][31][32]. Differences in sample preparation and normalization, as well as potential interference of heparin [33], can all substantially affect measurements of circulating miRNAs [21]. Alternatively, low miR-223 levels in acute coronary syndrome patients with a low response to P2Y 12 inhibitors might be the consequence of reduced expression in platelets of this patient subgroup.…”

Section: Discussioncontrasting

confidence: 99%

“…Most miRNAs are ubiquitously expressed, but a small subset is cell-specific and can be dysregulated in disease [19]. Their stable detectability in cell-free serum or plasma led to their investigation as biomarkers for various conditions, including immune cell activation in sepsis [20] and response of platelets to antiplatelet therapy [21]. However, the identification of a suitable miRNA biomarker in sepsis has been complicated by the numerous confounders present in such critically ill patients.…”

Section: Introductionmentioning

confidence: 99%

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

Braza-Boïls

Barwari

Gutmann

et al. 2020

IJMS

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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 P2Y 12 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 P2Y 12 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 P2Y 12 inhibition. While P2Y 12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

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“…Platelets contain a number of miRNAs and are equipped with fully functional miRNA effector complexes, namely Dicer and Ago2 . During the recent years, there have been continuous efforts to investigate the biomarker potentials of circulating miRNAs for platelet dysfunction and/or cardiovascular diseases . Thus, platelet activation can change miRNA expression profiles , although this is not shown in all studies .…”

Section: Discussionmentioning

confidence: 99%

Thrombin‐reduced miR‐27b attenuates platelet angiogenic activities in vitro via enhancing platelet synthesis of anti‐angiogenic thrombospondin‐1

Miao

Rahman

Jiang

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Platelets can synthesize proteins upon activation. Platelets contain a number of microRNAs (miRNA) and a fully functional miRNA effector machinery. It is, however, unclear if platelet miRNAs can regulate protein synthesis of platelets, and whether the regulation may produce a physiological impact. Objectives To investigate if and how platelet miRNAs regulate de novo syntheses of angiogenic regulators and subsequently modulate platelet angiogenic activities. Methods and Results Microarray-based miRNA profiling showed that thrombin stimulation in vitro down- or up-regulated a number of platelet miRNAs, both in the total platelet miRNAs and in Ago2-associated miRNAs. Among those altered miRNAs, miR-27b was down-regulated in both the total and Ago2-immunoprecipitated miRNA profiles of platelets, which was confirmed by reverse transcription-quantitative PCR (RT-qPCR). Using western blotting assays, we showed that thrombin induced platelet de novo synthesis of thrombospondin-1, and that the level of thrombospondin-1 synthesis could reach a level of 3-5-fold higher than that before thrombin stimulation. With either the platelet precursor megakaryocyte cell line MEG-01 cells or mature platelets, we demonstrated that transfection of miR-27b mimic, but not the negative control of miRNA mimic, markedly reduced thrombospondin-1 protein levels. The latter subsequently enhanced platelet-dependent endothelial tube formation on matrigel. Conclusions Thrombin stimulation in vitro reduces platelet miR-27b levels that may markedly enhance thrombin-evoked platelet de novo synthesis of thrombospondin-1. Elevation of platelet miR-27b by transfection inhibits thrombospondin-1 synthesis, and subsequently enhances platelet pro-angiogenic activities. Hence, platelet activation-dependent reduction of miR-27b levels may represent a novel negative regulatory mechanism of platelet angiogenic activities.

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MicroRNA Biomarkers and Platelet Reactivity

Cited by 162 publications

References 108 publications

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

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

Thrombin‐reduced miR‐27b attenuates platelet angiogenic activities in vitro via enhancing platelet synthesis of anti‐angiogenic thrombospondin‐1

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