Do miRNAs Have a Role in Platelet Function Regulation?

Abstract

MicroRNAs (miRNAs) are a class of non-coding RNAs known to repress mRNA translation and subsequent protein production. miRNAs are predicted to modulate many targets and are involved in regulating various cellular processes. Identifying their role in cell function regulation may allow circulating miRNAs to be used as diagnostic or prognostic markers of various diseases. Increasing numbers of clinical studies have shown associations between circulating miRNA levels and platelet reactivity or the recurrence of cardiovascular events. However, these studies differed regarding population selection, sample types used, miRNA quantification procedures, and platelet function assays. Furthermore, they often lacked functional validation of the miRNA identified in such studies. The latter step is essential to identifying causal relationships and understanding if and how miRNAs regulate platelet function. This review describes recent advances in translational research dedicated to identifying miRNAs' roles in platelet function regulation.

Keywords

microRNA - platelet function - biomarker

Publication History

Received: 30 November 2020

Accepted: 08 April 2021

Article published online:
30 June 2021

• References

• 1 Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Platelets at work in primary hemostasis. Blood Rev 2011; 25 (04) 155-167
• 2 Bakogiannis C, Sachse M, Stamatelopoulos K, Stellos K. Platelet-derived chemokines in inflammation and atherosclerosis. Cytokine 2019; 122: 154157
• 3 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
• 4 Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol 2018; 11 (01) 125
• 5 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
• 6 Faraday N, Yanek LR, Mathias R. et al. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1. Circulation 2007; 115 (19) 2490-2496
• 7 Zufferey A, Reny JL, Combescure C, de Moerloose P, Sanchez JC, Fontana P. Platelet reactivity is a stable and global phenomenon in aspirin-treated cardiovascular patients. Thromb Haemost 2011; 106 (03) 466-474
• 8 Bray PF, Mathias RA, Faraday N. et al. Heritability of platelet function in families with premature coronary artery disease. J Thromb Haemost 2007; 5 (08) 1617-1623
• 9 Nagalla S, Shaw C, Kong X. et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 2011; 117 (19) 5189-5197
• 10 Cimmino G, Tarallo R, Nassa G. et al. Activating stimuli induce platelet microRNA modulation and proteome reorganisation. Thromb Haemost 2015; 114 (01) 96-108
• 11 Lindsay CR, Edelstein LC. MicroRNAs in platelet physiology and function. Semin Thromb Hemost 2016; 42 (03) 215-222
• 12 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
• 13 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
• 14 Jakob P, Kacprowski T, Briand-Schumacher S. et al. Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction. Eur Heart J 2017; 38 (07) 511-515
• 15 Garcia A, Dunoyer-Geindre S, Fish RJ. et al. Methods to investigate miRNA function: focus on platelet reactivity. Thromb Haemost 2021; 121 (04) 409-421
• 16 Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14 (10A): 1902-1910
• 17 Lee Y, Kim M, Han J. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004; 23 (20) 4051-4060
• 18 Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 2006; 13 (12) 1097-1101
• 19 Okada C, Yamashita E, Lee SJ. et al. A high-resolution structure of the pre-microRNA nuclear export machinery. Science 2009; 326 (5957): 1275-1279
• 20 Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 2009; 11 (03) 228-234
• 21 Desvignes T, Batzel P, Berezikov E. et al. miRNA nomenclature: a view incorporating genetic origins, biosynthetic pathways, and sequence variants. Trends Genet 2015; 31 (11) 613-626
• 22 Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19 (01) 92-105
• 23 Pratt AJ, MacRae IJ. The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem 2009; 284 (27) 17897-17901
• 24 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
• 25 Weyrich AS, Schwertz H, Kraiss LW, Zimmerman GA. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 7 (02) 241-246
• 26 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
• 27 Provost P. The clinical significance of platelet microparticle-associated microRNAs. Clin Chem Lab Med 2017; 55 (05) 657-666
• 28 Diehl P, Fricke A, Sander L. et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93 (04) 633-644
• 29 Jeppesen DK, Fenix AM, Franklin JL. et al. Reassessment of exosome composition. Cell 2019; 177 (02) 428-445.e18
• 30 Arroyo JD, Chevillet JR, Kroh EM. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 2011; 108 (12) 5003-5008
• 31 Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011; 13 (04) 423-433
• 32 Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 2010; 38 (20) 7248-7259
• 33 O'Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO. RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat Rev Mol Cell Biol 2020; 21 (10) 585-606
• 34 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
• 35 De Meyer GR, Hoylaerts MF, Kockx MM, Yamamoto H, Herman AG, Bult H. Intimal deposition of functional von Willebrand factor in atherogenesis. Arterioscler Thromb Vasc Biol 1999; 19 (10) 2524-2534
• 36 Leblanc R, Houssin A, Peyruchaud O. Platelets, autotaxin and lysophosphatidic acid signalling: win-win factors for cancer metastasis. Br J Pharmacol 2018; 175 (15) 3100-3110
• 37 Kaudewitz D, Skroblin P, Bender LH. et al. Association of microRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
• 38 Pordzik J, Pisarz K, De Rosa S. et al. The potential role of platelet-related microRNAs in the development of cardiovascular events in high-risk populations, including diabetic patients: a review. Front Endocrinol (Lausanne) 2018; 9: 74
• 39 Shi R, Ge L, Zhou X. et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res 2013; 131 (06) 508-513
• 40 Chen Y, Song Y, Huang J. et al. Increased circulating exosomal miRNA-223 is associated with acute ischemic stroke. Front Neurol 2017; 8: 57
• 41 Zhang YY, Zhou X, Ji WJ. et al. Decreased circulating microRNA-223 level predicts high on-treatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis 2014; 38 (01) 65-72
• 42 Zampetaki A, Kiechl S, Drozdov I. et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 2010; 107 (06) 810-817
• 43 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
• 44 Witkowski M, Weithauser A, Tabaraie T. et al. Micro-RNA-126 reduces the blood thrombogenicity in diabetes mellitus via targeting of tissue factor. Arterioscler Thromb Vasc Biol 2016; 36 (06) 1263-1271
• 45 Zapilko V, Fish RJ, Garcia A. et al. MicroRNA-126 is a regulator of platelet-supported thrombin generation. Platelets 2020; 31 (06) 746-755
• 46 Garcia A, Dunoyer-Geindre S, Zapilko V, Nolli S, Reny JL, Fontana P. Functional validation of microRNA-126-3p as a platelet reactivity regulator using human haematopoietic stem cells. Thromb Haemost 2019; 119 (02) 254-263
• 47 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
• 48 Chamorro-Jorganes A, Araldi E, Suárez Y. MicroRNAs as pharmacological targets in endothelial cell function and dysfunction. Pharmacol Res 2013; 75: 15-27
• 49 Vickers KC, Landstreet SR, Levin MG. et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci U S A 2014; 111 (40) 14518-14523
• 50 Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci U S A 2010; 107 (27) 12228-12232
• 51 Rayner KJ, Suárez Y, Dávalos A. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010; 328 (5985): 1570-1573
• 52 Yang K, He YS, Wang XQ. et al. MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. FEBS Lett 2011; 585 (06) 854-860
• 53 Soh J, Iqbal J, Queiroz J, Fernandez-Hernando C, Hussain MM. MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med 2013; 19 (07) 892-900
• 54 Suárez Y, Wang C, Manes TD, Pober JS. Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. J Immunol 2010; 184 (01) 21-25
• 55 Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A 2008; 105 (05) 1516-1521
• 56 Wen P, Cao H, Fang L. et al. miR-125b/Ets1 axis regulates transdifferentiation and calcification of vascular smooth muscle cells in a high-phosphate environment. Exp Cell Res 2014; 322 (02) 302-312
• 57 Du Y, Gao C, Liu Z. et al. Upregulation of a disintegrin and metalloproteinase with thrombospondin motifs-7 by miR-29 repression mediates vascular smooth muscle calcification. Arterioscler Thromb Vasc Biol 2012; 32 (11) 2580-2588
• 58 Kowara M, Cudnoch-Jedrzejewska A, Opolski G, Wlodarski P. MicroRNA regulation of extracellular matrix components in the process of atherosclerotic plaque destabilization. Clin Exp Pharmacol Physiol 2017; 44 (07) 711-718
• 59 Li S, Lee C, Song J. et al. Circulating microRNAs as potential biomarkers for coronary plaque rupture. Oncotarget 2017; 8 (29) 48145-48156
• 60 Michael JV, Wurtzel JGT, Mao GF. et al. Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth. Blood 2017; 130 (05) 567-580
• 61 Lazar S, Goldfinger LE. Platelet microparticles and miRNA transfer in cancer progression: many targets, modes of action, and effects across cancer stages. Front Cardiovasc Med 2018; 5: 13
• 62 Chen Z, Ma T, Huang C, Hu T, Li J. The pivotal role of microRNA-155 in the control of cancer. J Cell Physiol 2014; 229 (05) 545-550
• 63 Jurkovicova D, Magyerkova M, Kulcsar L. et al. miR-155 as a diagnostic and prognostic marker in hematological and solid malignancies. Neoplasma 2014; 61 (03) 241-251
• 64 Vimalraj S, Miranda PJ, Ramyakrishna B, Selvamurugan N. Regulation of breast cancer and bone metastasis by microRNAs. Dis Markers 2013; 35 (05) 369-387
• 65 Gao Y, Liu Y, Du L. et al. Down-regulation of miR-24-3p in colorectal cancer is associated with malignant behavior. Med Oncol 2015; 32 (01) 362
• 66 He JF, Luo YM, Wan XH, Jiang D. Biogenesis of MiRNA-195 and its role in biogenesis, the cell cycle, and apoptosis. J Biochem Mol Toxicol 2011; 25 (06) 404-408
• 67 Liang H, Yan X, Pan Y. et al. MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3. Mol Cancer 2015; 14: 58
• 68 Tak H, Kang H, Ji E, Hong Y, Kim W, Lee EK. Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma. Biochem Biophys Res Commun 2018; 497 (04) 1117-1122
• 69 Yu D, Liu X, Han G. et al. The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation. Cell Commun Signal 2019; 17 (01) 173
• 70 Chen X, Ba Y, Ma L. et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008; 18 (10) 997-1006
• 71 El-Hefnawy T, Raja S, Kelly L. et al. Characterization of amplifiable, circulating RNA in plasma and its potential as a tool for cancer diagnostics. Clin Chem 2004; 50 (03) 564-573
• 72 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
• 73 Zufferey A, Ibberson M, Reny JL. et al. New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach. Hum Genet 2016; 135 (04) 403-414
• 74 Simon LM, Edelstein LC, Nagalla S. et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 2014; 123 (16) e37-e45
• 75 Sunderland N, Skroblin P, Barwari T. et al. MicroRNA biomarkers and platelet reactivity: the clot thickens. Circ Res 2017; 120 (02) 418-435
• 76 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
• 77 Fejes Z, Póliska S, Czimmerer Z. et al. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost 2017; 117 (03) 529-542
• 78 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
• 79 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
• 80 Schwarzenbach H, da Silva AM, Calin G, Pantel K. Data normalization strategies for microRNA quantification. Clin Chem 2015; 61 (11) 1333-1342
• 81 Jansen F, Schäfer L, Wang H. et al. Kinetics of circulating microRNAs in response to cardiac stress in patients with coronary artery disease. J Am Heart Assoc 2017; 6 (08) 6
• 82 Gee HE, Buffa FM, Camps C. et al. The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis. Br J Cancer 2011; 104 (07) 1168-1177
• 83 Tanaka M, Oikawa K, Takanashi M. et al. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One 2009; 4 (05) e5532
• 84 Zalewski K, Misiek M, Kowalik A. et al. Normalizers for microRNA quantification in plasma of patients with vulvar intraepithelial neoplasia lesions and vulvar carcinoma. Tumour Biol 2017; 39 (11) 1010428317717140
• 85 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
• 86 Li Y, Xiang GM, Liu LL. et al. Assessment of endogenous reference gene suitability for serum exosomal microRNA expression analysis in liver carcinoma resection studies. Mol Med Rep 2015; 12 (03) 4683-4691
• 87 Kok MG, Halliani A, Moerland PD, Meijers JC, Creemers EE, Pinto-Sietsma SJ. Normalization panels for the reliable quantification of circulating microRNAs by RT-qPCR. FASEB J 2015; 29 (09) 3853-3862
• 88 Vandesompele J, De Preter K, Pattyn F. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3 (07) H0034
• 89 Andersen CL, Jensen JL, Ørntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 2004; 64 (15) 5245-5250
• 90 Strassel C, Brouard N, Mallo L. et al. Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets. Blood 2016; 127 (18) 2231-2240
• 91 Kleinhammer A, Wurst W, Kühn R. Constitutive and conditional RNAi transgenesis in mice. Methods 2011; 53 (04) 430-436
• 92 Park CY, Jeker LT, Carver-Moore K. et al. A resource for the conditional ablation of microRNAs in the mouse. Cell Rep 2012; 1 (04) 385-391
• 93 Tiedt R, Schomber T, Hao-Shen H, Skoda RC. Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. Blood 2007; 109 (04) 1503-1506
• 94 Takada S, Sato T, Ito Y. et al. Targeted gene deletion of miRNAs in mice by TALEN system. PLoS One 2013; 8 (10) e76004
• 95 Chang H, Yi B, Ma R, Zhang X, Zhao H, Xi Y. CRISPR/cas9, a novel genomic tool to knock down microRNA in vitro and in vivo. Sci Rep 2016; 6: 22312
• 96 Zeng LL, He XS, Liu JR, Zheng CB, Wang YT, Yang GY. Lentivirus-mediated overexpression of microRNA-210 improves long-term outcomes after focal cerebral ischemia in mice. CNS Neurosci Ther 2016; 22 (12) 961-969
• 97 Chiriaco M, Farinelli G, Capo V. et al. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. Mol Ther 2014; 22 (08) 1472-1483
• 98 Fridrich A, Hazan Y, Moran Y. Too many false targets for microRNAs: challenges and pitfalls in prediction of miRNA targets and their gene ontology in model and non-model organisms. BioEssays 2019; 41 (04) e1800169
• 99 Kuchay SM, Chishti AH. Calpain-mediated regulation of platelet signaling pathways. Curr Opin Hematol 2007; 14 (03) 249-254
• 100 Siuda D, Randriamboavonjy V, Fleming I. Regulation of calpain 2 expression by miR-223 and miR-145. Biochim Biophys Acta Gene Regul Mech 2019; 1862 (10) 194438
• 101 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
• 102 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
• 103 Chattopadhyay M, Dahiya N, Atreya C. MicroRNA-223 regulates Septin-2 and Septin-6 in stored platelets. MicroRNA 2018; 7 (03) 223-228