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DOI: 10.1055/s-0045-1805041
Unlocking the Potential of MicroRNA Expression: Biomarkers for Platelet Reactivity and Coronary Artery Disease

Abstract
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, with platelet reactivity playing a central role in its pathogenesis. Recent research has identified microRNAs (miRNAs; miRs) as potential biomarkers for CAD, due to their ability to regulate platelet function and reactivity. This review focuses on four key miRNAs—miR-223, miR-126, miR-21, and miR-150—known to influence platelet reactivity and their implications in CAD. miR-223, which is highly expressed in platelets, has shown associations with CAD and myocardial infarction, while miR-126 has been linked to thrombus formation and vascular health. Additionally, miR-21 and miR-150 have also emerged as important players, with roles in platelet reactivity and cardiovascular outcomes. However, despite their potential, the use of miRNAs as clinical biomarkers faces several challenges, including variability in reported results across studies. These inconsistencies often arise from differences in sample material, preanalytical conditions, and normalization strategies. Furthermore, the influence of antiplatelet therapy on miRNA expression adds another layer of complexity, making it difficult to determine whether observed changes in miRNA levels are due to disease states or therapeutic interventions. This review therefore highlights the need for standardization in miRNA research to enhance the reliability of findings. By addressing these methodological challenges, miRNAs could become powerful tools in personalized medicine, aiding in the development of tailored therapeutic strategies for CAD patients and ultimately improving clinical outcomes.
Publication History
Article published online:
12 March 2025
© 2025. Thieme. All rights reserved.
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References
- 1 Roth GA, Johnson C, Abajobir A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017; 70 (01) 1-25
- 2 Moore S. Platelet aggregation secondary to coronary obstruction. Circulation 1976; 53 (Suppl. 03) I66-I69
- 3 Gurbel PA, Jeong YH, Navarese EP, Tantry US. Platelet-mediated thrombosis: from bench to bedside. Circ Res 2016; 118 (09) 1380-1391
- 4 Patrono C, Morais J, Baigent C. et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol 2017; 70 (14) 1760-1776
- 5 Kim J, Park J, Kwon JH. et al. Antiplatelet therapy and long-term mortality in patients with myocardial injury after non-cardiac surgery. Open Heart 2023; 10 (02) e002318
- 6 Fox KAA, Metra M, Morais J, Atar D. The myth of ‘stable’ coronary artery disease. Nat Rev Cardiol 2020; 17 (01) 9-21
- 7 De Rosa R, Palmerini T, De Servi S. et al. High on-treatment platelet reactivity and outcome in elderly with non ST-segment elevation acute coronary syndrome - Insight from the GEPRESS study. Int J Cardiol 2018; 259: 20-25
- 8 Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol 2005; 46 (06) 986-993
- 9 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109 (25) 3171-3175
- 10 Würtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18 (33) 5344-5361
- 11 Zdravkovic S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, De Faire U. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J Intern Med 2002; 252 (03) 247-254
- 12 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (02) 281-297
- 13 Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19 (01) 92-105
- 14 Barroga CF, Pham H, Kaushansky K. Thrombopoietin regulates c-Myb expression by modulating micro RNA 150 expression. Exp Hematol 2008; 36 (12) 1585-1592
- 15 Lu J, Guo S, Ebert BL. et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell 2008; 14 (06) 843-853
- 16 Kondkar AA, Bray MS, Leal SM. et al. VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J Thromb Haemost 2010; 8 (02) 369-378
- 17 Nagalla S, Shaw C, Kong X. et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 2011; 117 (19) 5189-5197
- 18 Lindsay CR, Edelstein LC. MicroRNAs in platelet physiology and function. Semin Thromb Hemost 2016; 42 (03) 215-222
- 19 Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16 (09) 961-966
- 20 Gilad S, Meiri E, Yogev Y. et al. Serum microRNAs are promising novel biomarkers. PLoS One 2008; 3 (09) e3148
- 21 Mitchell PS, Parkin RK, Kroh EM. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008; 105 (30) 10513-10518
- 22 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75 (05) 843-854
- 23 Reinhart BJ, Slack FJ, Basson M. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans . Nature 2000; 403 (6772) 901-906
- 24 Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455 (7209) 64-71
- 25 Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res 2016; 118 (04) 703-720
- 26 Hata A. Functions of microRNAs in cardiovascular biology and disease. Annu Rev Physiol 2013; 75: 69-93
- 27 Edelstein LC, Simon LM, Montoya RT. et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013; 19 (12) 1609-1616
- 28 Plé H, Landry P, Benham A, Coarfa C, Gunaratne PH, Provost P. The repertoire and features of human platelet microRNAs. PLoS One 2012; 7 (12) e50746
- 29 Gidlöf O, van der Brug M, Ohman J. et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 2013; 121 (19) 3908-3917 , S1–S26
- 30 Teruel-Montoya R, Kong X, Abraham S. et al. MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression. PLoS One 2014; 9 (07) e102259
- 31 Shan Z, Qin S, Li W. et al. An endocrine genetic signal between blood cells and vascular smooth muscle cells: role of microRNA-223 in smooth muscle function and atherogenesis. J Am Coll Cardiol 2015; 65 (23) 2526-2537
- 32 Zeng Z, Xia L, Fan X. et al. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. J Clin Invest 2019; 129 (03) 1372-1386
- 33 Garzon R, Pichiorri F, Palumbo T. et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci U S A 2006; 103 (13) 5078-5083
- 34 Opalinska JB, Bersenev A, Zhang Z. et al. MicroRNA expression in maturing murine megakaryocytes. Blood 2010; 116 (23) e128-e138
- 35 Bongiovanni D, Santamaria G, Klug M. et al. Transcriptome analysis of reticulated platelets reveals a prothrombotic profile. Thromb Haemost 2019; 119 (11) 1795-1806
- 36 Li L, Wu F, Xie Y. et al. MiR-202-3p inhibits foam cell formation and is associated with coronary heart disease risk in a Chinese population. Int Heart J 2020; 61 (01) 153-159
- 37 Pedersen OB, Hvas AM, Grove EL. et al. Association of whole blood microRNA expression with platelet function and turnover in patients with coronary artery disease. Thromb Res 2022; 211: 98-105
- 38 Pedersen OB, Hvas AM, Pasalic L, Kristensen SD, Grove EL, Nissen PH. Platelet function and maturity and related microRNA expression in whole blood in patients with ST-segment elevation myocardial infarction. Thromb Haemost 2024; 124 (03) 192-202
- 39 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58 (19) 1945-1954
- 40 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
- 41 Osman A, Fälker K. Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes. Platelets 2011; 22 (06) 433-441
- 42 Zampetaki A, Willeit P, Tilling L. et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012; 60 (04) 290-299
- 43 Hussein K, Theophile K, Dralle W, Wiese B, Kreipe H, Bock O. MicroRNA expression profiling of megakaryocytes in primary myelofibrosis and essential thrombocythemia. Platelets 2009; 20 (06) 391-400
- 44 Leierseder S, Petzold T, Zhang L, Loyer X, Massberg S, Engelhardt S. miR-223 is dispensable for platelet production and function in mice. Thromb Haemost 2013; 110 (06) 1207-1214
- 45 Elgheznawy A, Shi L, Hu J. et al. Dicer cleavage by calpain determines platelet microRNA levels and function in diabetes. Circ Res 2015; 117 (02) 157-165
- 46 Garcia A, Dunoyer-Geindre S, Nolli S, Reny JL, Fontana P. An ex vivo and in silico study providing insights into the interplay of circulating miRNAs level, platelet reactivity and thrombin generation: looking beyond traditional pharmacogenetics. J Pers Med 2021; 11 (05) 323
- 47 Zhang Y, Wang Y, Zhang L. et al. Reduced platelet miR-223 induction in Kawasaki disease leads to severe coronary artery pathology through a miR-223/PDGFRβ vascular smooth muscle cell axis. Circ Res 2020; 127 (07) 855-873
- 48 Kaudewitz D, Skroblin P, Bender LH. et al. Association of microRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
- 49 Stojkovic S, Wadowski PP, Haider P. et al. Circulating microRNAs and monocyte-platelet aggregate formation in acute coronary syndrome. Thromb Haemost 2021; 121 (07) 913-922
- 50 Zhang LJ, Hu YX, Huang RZ. et al. Intraplatelet miRNA-126 regulates thrombosis and its reduction contributes to platelet inhibition. Cardiovasc Res 2024; 120 (13) 1622-1635
- 51 Becker KC, Kwee LC, Neely ML. et al. Circulating microRNA profiling in non-ST elevated coronary artery syndrome highlights genomic associations with serial platelet reactivity measurements. Sci Rep 2020; 10 (01) 6169
- 52 Reddy S, Hu DQ, Zhao M. et al. miR-21 is associated with fibrosis and right ventricular failure. JCI Insight 2017; 2 (09) e91625
- 53 Barwari T, Eminaga S, Mayr U. et al. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI Insight 2018; 3 (21) e123335
- 54 Peng L, Liu J, Qin L. et al. Interaction between platelet-derived microRNAs and CYP2C19*2 genotype on clopidogrel antiplatelet responsiveness in patients with ACS. Thromb Res 2017; 157: 97-102
- 55 Pedersen OB, Grove EL, Kristensen SD, Nissen PH, Hvas AM. MicroRNA as biomarkers for platelet function and maturity in patients with cardiovascular disease. Thromb Haemost 2022; 122 (02) 181-195
- 56 Garcia A, Dunoyer-Geindre S, Nolli S, Strassel C, Reny JL, Fontana P. miR-204-5p and platelet function regulation: insight into a mechanism mediated by CDC42 and GPIIbIIIa. Thromb Haemost 2021; 121 (09) 1206-1219
- 57 Ding T, Zeng X, Cheng B. et al. Platelets in acute coronary syndrome patients with high platelet reactivity after dual antiplatelet therapy exhibit upregulation of miR-204-5p. Ann Clin Lab Sci 2019; 49 (05) 619-631
- 58 Schulte C, Molz S, Appelbaum S. et al. miRNA-197 and miRNA-223 predict cardiovascular death in a cohort of patients with symptomatic coronary artery disease. PLoS One 2015; 10 (12) e0145930
- 59 Pedersen OB, Grove EL, Nissen PH. et al. Expression of microRNA predicts cardiovascular events in patients with stable coronary artery disease. Thromb Haemost 2023; 123 (03) 307-316
- 60 Singh S, de Ronde MWJ, Kok MGM. et al. MiR-223-3p and miR-122-5p as circulating biomarkers for plaque instability. Open Heart 2020; 7 (01) e001223
- 61 Jenike AE, Halushka MK. miR-21: a non-specific biomarker of all maladies. Biomark Res 2021; 9 (01) 18
- 62 Han H, Qu G, Han C. et al. MiR-34a, miR-21 and miR-23a as potential biomarkers for coronary artery disease: a pilot microarray study and confirmation in a 32 patient cohort. Exp Mol Med 2015; 47 (02) e138
- 63 Kumar D, Narang R, Sreenivas V. et al. Circulatory miR-133b and miR-21 as novel biomarkers in early prediction and diagnosis of coronary artery disease. Genes (Basel) 2020; 11 (02) 164
- 64 Yao R, Ma Y, Du Y. et al. The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome. Cell Mol Immunol 2011; 8 (06) 486-495
- 65 Karakas M, Schulte C, Appelbaum S. et al. Circulating microRNAs strongly predict cardiovascular death in patients with coronary artery disease-results from the large AtheroGene study. Eur Heart J 2017; 38 (07) 516-523
- 66 de Boer HC, van Solingen C, Prins J. et al. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur Heart J 2013; 34 (44) 3451-3457
- 67 Tran JQD, Pedersen OH, Larsen ML. et al. Platelet microRNA expression and association with platelet maturity and function in patients with essential thrombocythemia. Platelets 2020; 31 (03) 365-372
- 68 Gumiężna K, Bednarek A, Sygitowicz G. et al. Platelet microRNAs as potential novel biomarkers for antiplatelet therapy with P2Y12 inhibitors and their association with platelet function. J Clin Med 2023; 13 (01) 63
- 69 Orenes-Piñero E, Marín F, Lip GY. miRNA-197 and miRNA-223 and cardiovascular death in coronary artery disease patients. Ann Transl Med 2016; 4 (10) 200
- 70 Wang K, Yuan Y, Cho JH, McClarty S, Baxter D, Galas DJ. Comparing the microRNA spectrum between serum and plasma. PLoS One 2012; 7 (07) e41561
- 71 Glinge C, Clauss S, Boddum K. et al. Stability of circulating blood-based microRNAs - pre-analytic methodological considerations. PLoS One 2017; 12 (02) e0167969
- 72 Jung R, Lübcke C, Wagener C, Neumaier M. Reversal of RT-PCR inhibition observed in heparinized clinical specimens. Biotechniques 1997; 23 (01) 24-26 , 28
- 73 Kaudewitz D, Lee R, Willeit P. et al. Impact of intravenous heparin on quantification of circulating microRNAs in patients with coronary artery disease. Thromb Haemost 2013; 110 (03) 609-615
- 74 Mompeón A, Ortega-Paz L, Vidal-Gómez X. et al. Disparate miRNA expression in serum and plasma of patients with acute myocardial infarction: a systematic and paired comparative analysis. Sci Rep 2020; 10 (01) 5373
- 75 Binderup HG, Houlind K, Madsen JS, Brasen CL. Pre-storage centrifugation conditions have significant impact on measured microRNA levels in biobanked EDTA plasma samples. Biochem Biophys Rep 2016; 7: 195-200
- 76 McDonald JS, Milosevic D, Reddi HV, Grebe SK, Algeciras-Schimnich A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem 2011; 57 (06) 833-840
- 77 Blondal T, Jensby Nielsen S, Baker A. et al. Assessing sample and miRNA profile quality in serum and plasma or other biofluids. Methods 2013; 59 (01) S1-S6
- 78 Brunet-Vega A, Pericay C, Quílez ME, Ramírez-Lázaro MJ, Calvet X, Lario S. Variability in microRNA recovery from plasma: comparison of five commercial kits. Anal Biochem 2015; 488: 28-35
- 79 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001; 25 (04) 402-408
- 80 Bustin SA, Benes V, Garson JA. et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55 (04) 611-622
- 81 Bustin SA. Improving the quality of quantitative polymerase chain reaction experiments: 15 years of MIQE. Mol Aspects Med 2024; 96: 101249
- 82 Faraldi M, Gomarasca M, Sansoni V, Perego S, Banfi G, Lombardi G. Normalization strategies differently affect circulating miRNA profile associated with the training status. Sci Rep 2019; 9 (01) 1584
- 83 Grove EL, Storey RF, Würtz M. Platelet function testing in atherothrombotic disease. Curr Pharm Des 2012; 18 (33) 5379-5391
- 84 Larsen JB, Hvas AM, Hojbjerg JA. Platelet function testing: update and future directions. Semin Thromb Hemost 2023; 49 (06) 600-608
- 85 Rubak P, Nissen PH, Kristensen SD, Hvas AM. Investigation of platelet function and platelet disorders using flow cytometry. Platelets 2016; 27 (01) 66-74
- 86 Karon BS, Tolan NV, Koch CD. et al. Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. Clin Chem 2014; 60 (12) 1524-1531
- 87 Schultz-Lebahn A, Skipper MT, Hvas AM, Larsen OH. Optimized tool for evaluation of platelet function measured by impedance aggregometry. Platelets 2021; 32 (06) 842-845
- 88 Skipper MT, Rubak P, Stentoft J, Hvas AM, Larsen OH. Evaluation of platelet function in thrombocytopenia. Platelets 2018; 29 (03) 270-276
- 89 Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6 (11) 857-866
- 90 Hernando E. MicroRNAs and cancer: role in tumorigenesis, patient classification and therapy. Clin Transl Oncol 2007; 9 (03) 155-160
- 91 Want A, Staniak K, Grabowska-Pyrzewicz W. et al. Optimized RT-qPCR and a novel normalization method for validating circulating miRNA biomarkers in ageing-related diseases. Sci Rep 2023; 13 (01) 20869
- 92 Banerjee M, Rowley JW, Stubben CJ. et al. Prospective, international, multisite comparison of platelet isolation techniques for genome-wide transcriptomics: communication from the SSC of the ISTH. J Thromb Haemost 2024; 22 (10) 2922-2934