Circulating MicroRNAs as Novel Biomarkers for Platelet Activation

Willeit, Peter; Zampetaki, Anna; Dudek, Katarzyna; Kaudewitz, Dorothee; King, A. J.; Kirkby, Nicholas S.; Crosby‐Nwaobi, Roxanne; Prokopi, Marianna; Drozdov, Ignat; Langley, Sarah R.; Sivaprasad, Sobha; Markus, Hugh S.; Mitchell, Jane A.; Warner, Timothy D.; Kiechl, Stefan; Mayr, Manuel

doi:10.1161/circresaha.111.300539

Cited by 361 publications

(392 citation statements)

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“…The history of medication use was included in the prediction model 2 (Table 2) to investigate the effect on AMI occurrence because increasing evidence has shown that medication therapy may also alter circulating miRNA levels. 23,24 Results suggest that the medication use decreased the associations between miRNAs and AMI to a certain degree, but the associations remained significant. Of note, the miRNA levels showed no significant difference in patients with AMI with or without history of medication use before hospital admission, suggesting that the 2 miRNAs are markers of AMI rather than drug use.…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Huang

Lü

et al. 2014

Circ Cardiovasc Genet

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A cute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. 1 Multiple conventional risk factors and serum atherosclerotic biomarkers have been established for coronary heart disease (CHD). 2 However, advances in genomics and proteomics, especially gene-expression profiling using microarray and quantitative real-time polymerase chain reaction (qPCR), have promoted the generation of many novel molecular biomarkers for AMI with potential clinical values. 3,4 Recently, microRNAs (miRNAs) have attracted extensive interest in the field of cardiovascular diseases. 5 Clinical Perspective on p 198MiRNAs are short, endogenous, noncoding RNAs that regulate gene expressions at the posttranscriptional level by binding to the 3′-untranslated regions of their target mRNAs. 6,7 MiRNAs have now emerged as key regulators of cardiac growth, vascular development, and angiogenesis. 8,9 Recent studies demonstrated that miRNAs can be detected in circulating blood and may be useful as disease biomarkers. 10,11 The levels and identities of circulating miRNAs in cardiovascular diseases have been evaluated in a series of studies. For instance, levels of some vascular and inflammation-associated miRNAs were found to be significantly lower in the plasma of 67 patients with CHD when compared with controls, 12 and the cardiac-specific miRNA, miR-208a, was only detectable in 33 patients with AMI and not Background-Circulating microRNAs ( miRNAs) are emerging as novel disease biomarkers. We aimed to explore the association between circulating miRNAs and the occurrence of acute myocardial infarction (AMI) in Chinese populations. Methods and Results-In the discovery stage, the plasma of 20 patients with AMI and 20 controls were pooled respectively and profiled by massively parallel sequencing. Seventy-seven miRNAs showed differential expression. Selected miRNAs were validated in 178 patients with AMI and 198 controls using quantitative reverse transcriptase polymerase chain reaction assays and further replicated in 150 patients with AMI and 150 controls. Results suggest that miR-320b and miR-125b levels were significantly lower in patients with AMI than in controls in both validation populations (P<0.0001). Lower levels of miR-320b and miR-125b were associated with increased occurrence of AMI (adjusted odds ratio, 4.71; 95% confidence interval, 2.96-7.48 and odds ratio, 4.27; 95% confidence interval, 2.84-6.41, respectively). Addition of the 2 miRNAs to traditional risk factors led to a significant improvement in the area under the curve from 0.822 (95% confidence interval, 0.787-0.856) to 0.871 (95% confidence interval, 0.842-0.900), with a net reclassification improvement of 20.45% (P<0.0001) and an integrated discrimination improvement of 0.16 (P<0.0001) for patients with AMI. A functional study showed that miR-320b and miR-125b could regulate the expression profiles of genes enriched in several signal transduction pathways critical for coronary heart disease in human vascular endothelial cells. Conclusions-The...

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Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Huang

Lü

et al. 2014

Circ Cardiovasc Genet

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“…Interestingly, platelet MPs are the most abundant cellderived MP subtype in the circulation [72], where relatively high levels of microRNAs originating from platelets are also found [73].…”

Section: Clinical Significance Of Platelet Mps and Micrornasmentioning

confidence: 99%

“…Circulating microRNAs have been proposed by as novel biomarkers for platelet activation [73] and coronary artery disease [77]. The group of Manuel Mayr demonstrated a substantial platelet contribution to the pool of circulating microRNAs, noting, in doing so, that the microRNA content of platelet-poor plasma differs from that of serum [73].…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

“…The group of Manuel Mayr demonstrated a substantial platelet contribution to the pool of circulating microRNAs, noting, in doing so, that the microRNA content of platelet-poor plasma differs from that of serum [73]. However, the authors cautioned that (i) antiplatelet medication (e.g.…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

“…However, the authors cautioned that (i) antiplatelet medication (e.g. aspirin) attenuates the release of platelet-derived microRNAs [73], and (ii) heparin inhibits the polymerase chain reactions, in particular the amplification of the exogenous Caenorhabditis elegans spike-in control, thereby resulting in an artefactual rise of endogenous microRNAs [78]. These findings prompted the authors to caution that antiplatelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma microRNAs to cardiovascular disease.…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

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The clinical significance of platelet microparticle-associated microRNAs

Provost

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Abstract:Circulating blood platelets play a central role in the maintenance of hemostasis. They adhere to subendothelial extracellular matrix proteins that become exposed upon vessel wall damage, which is followed by platelet activation, further platelet recruitment, platelet aggregation and formation of an occlusive, or non-occlusive, platelet thrombus. Platelets host a surprisingly diverse transcriptome, which is comprised of ~ 9500 messenger RNAs (mRNAs) and different classes of non-coding RNAs, including microRNAs, as well as a significant repertoire of proteins that contribute to their primary (adhesion, aggregation, granule secretion) and alternative (RNA transfer, mRNA translation, immune regulation) functions. Platelets have the propensity to release microparticles (MPs; 0.1-1 μm in diameter) upon activation, which may mediate inflammatory responses and contribute to exacerbate inflammatory diseases and conditions. Carrying components of the platelets' cytoplasm, platelet MPs may exert their effects on recipient cells by transferring their content in platelet-derived bioactive lipid mediators, cytokines, mRNAs and microRNAs. Platelet MP-associated microRNAs may thus function also outside of platelets and play an important role in intercellular signaling and gene expression programming across the entire circulatory system. The role and importance of platelet MP-associated microRNAs in various aspects of biology and pathophysiology are increasingly recognized, and now provide the scientific basis and rationale to support further translational research and clinical studies. The clinical significance, pathophysiological role as well as the diagnostic and therapeutic potential of platelet MP-associated microRNAs in cardiovascular diseases, platelet transfusion and cancer will be discussed.

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Circulating microRNAs for predicting and monitoring response to mechanical circulatory support from a left ventricular assist device

Morley-Smith

Mills

Jacobs

et al. 2014

European J of Heart Fail

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AimsThere are few non-invasive techniques to predict and monitor patients' responses to left ventricular assist device (LVAD) therapy. MicroRNAs (miRs) are small non-coding RNAs with intricate roles in cardiovascular disease. They are stable in the circulation, readily quantified, and may be useful as new biomarkers. This study sought to identify candidate miR biomarkers for further investigation.Methods and resultsWe studied 53 plasma and 20 myocardial samples from 19 patients who underwent HeartMate II LVAD implantation, and used a screening microarray to analyse the change in expression of 1113 miRs after 6 months LVAD support. Twelve miRs showed significant variation and underwent validation, yielding miR-1202 and miR-483-3p as candidate biomarkers. In the test cohort, circulating miR-483-3p showed early and sustained up-regulation with LVAD support, with median (interquartile range) fold changes from baseline of 2.17 (1.43–2.62; P = 0.011), 2.27 (1.12–2.42; P = 0.036), 1.87 (1.64–4.36; P = 0.028), and 2.82 (0.70–10.62; P = 0.249) at 3, 6, 9, and 12 months, respectively, whilst baseline plasma miR-1202 identified good vs. poor LVAD responders [absolute expression 1.296 (1.293–1.306) vs. 1.311 (1.310–1.318) arbitrary units; P = 0.004]. Both miRs are enriched in ventricular myocardium, suggesting the heart as the possible source of the plasma fraction.ConclusionsThis is the first report of circulating miR biomarkers in LVAD patients. We demonstrate the feasibility of this approach, report the potential for miR-483-3p and miR-1202, respectively, to monitor and predict response to LVAD therapy, and propose further work to study these hypotheses and elucidate roles for miR-483-3p and miR-1202 in clinical practice and in underlying biological processes.

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Circulating MicroRNAs as Novel Biomarkers for Platelet Activation

Cited by 361 publications

References 15 publications

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

The clinical significance of platelet microparticle-associated microRNAs

Circulating microRNAs for predicting and monitoring response to mechanical circulatory support from a left ventricular assist device

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