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MicroRNAs in platelet function and cardiovascular disease

Nature Reviews Cardiology volume 12, pages 711–717 (2015)Cite this article

Subjects

Key Points

  • Platelet function has an important role in mediating particular common forms of cardiovascular disease, such as acute coronary syndromes and stroke

  • Although they lack nuclei, platelets contain RNAs, including small noncoding RNAs such as microRNAs, and the necessary machinery to perform translation

  • Data suggest that microRNAs can influence platelet functions, including thrombosis, atherosclerosis, and angiogenesis

  • Platelet RNA can also be transferred to other vascular cells, but further information about the role of microRNA transfer is needed

Abstract

Cardiovascular disease—a leading cause of morbidity and mortality among adults—is strongly influenced by platelet function through acute thrombotic and atherogenic mechanisms. Pathways that regulate platelet activity and lead to coronary occlusion are central to the pathogenesis of acute coronary syndromes. Platelet activation contributes to other thrombotic disorders and cardiovascular diseases, including stroke. Anucleate platelets are now understood to contain transcripts that might relate to other physiological or pathophysiological conditions, be released into the circulation, participate in protein formation, and engage in horizontal RNA transfer to other vascular cells. These platelet transcripts include microRNAs (miRNAs), which are small noncoding RNAs involved in many molecular processes, most notably regulation of gene expression. In platelets, these noncoding RNAs seem to participate in vascular homeostasis, inflammation, and platelet function. In addition, levels of platelet miRNAs in the circulation are associated with the presence or extent of cardiovascular diseases, such as atrial fibrillation and peripheral vascular disease. Accumulating data suggest mechanistic roles for platelet-derived miRNAs in haemostasis, thrombosis, and unstable coronary syndromes. In addition, evidence suggests that platelet-derived miRNAs might have important roles as biomarkers of cardiovascular disease susceptibility, prognosis, or treatment.

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Figure 1: Platelet microRNA biogenesis and function.
Figure 2: Common miRNAs associated with ST-segment elevation myocardial infarction in plasma, platelets, and leukocytes.72

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References

  1. Roger, V. L. et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011).

    Article  PubMed  Google Scholar 

  2. Roger, V. L. et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125, e2–e220 (2012).

    Article  PubMed  Google Scholar 

  3. Writing Group Members. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121, e46–e215 (2010).

  4. Michelson, A. D. Platelets 3rd edn (Academic Press, 2012).

    Google Scholar 

  5. Lackie, J. A Dictionary of Biomedicine (Oxford University Press, 2010).

    Google Scholar 

  6. Davies, M. J. & Thomas, A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N. Engl. J. Med. 310, 1137–1140 (1984).

    Article  CAS  PubMed  Google Scholar 

  7. Falk, E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br. Heart J. 50, 127–134 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sherman, C. T. et al. Coronary angioscopy in patients with unstable angina pectoris. N. Engl. J. Med. 315, 913–919 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Zimmerman, G. A. & Weyrich, A. S. Signal-dependent protein synthesis by activated platelets: new pathways to altered phenotype and function. Arteriosc ler. Thromb. Vasc. Biol. 28, s17–s24 (2008).

    CAS  Google Scholar 

  10. Weyrich, A. S., Schwertz, H., Kraiss, L. W. & Zimmerman, G. A. Protein synthesis by platelets: historical and new perspectives. J. Thromb. Haemost. 7, 241–246 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Rowley, J. W. et al. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood 118, e101–e111 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rowley, J. W., Schwertz, H. & Weyrich, A. S. Platelet mRNA: the meaning behind the message. Curr. Opin. Hematol. 19, 385–391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bugert, P., Dugrillon, A., Günaydin, A., Eichler, H. & Klüter, H. Messenger RNA profiling of human platelets by microarray hybridization. Thromb. Haemost. 90, 738–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Gnatenko, D. V. et al. Transcript profiling of human platelets using microarray and serial analysis of gene expression. Blood 101, 2285–2293 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Bray, P. F. et al. The complex transcriptional landscape of the anucleate human platelet. BMC Genomics 14, 1 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McRedmond, J. P. et al. Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes. Mol. Cell. Proteomics 3, 133–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Londin, E. R. et al. The human platelet: strong transcriptome correlations among individuals associate weakly with the platelet proteome. Biol. Direct 9, 3 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Renaud, B., Buda, M., Lewis, B. D. & Pujol, J. F. Effects of 5,6-dihydroxytryptamine on tyrosine-hydroxylase activity in central catecholaminergic neurons of the rat. Biochem. Pharmacol. 24, 1739–1742 (1975).

    Article  CAS  PubMed  Google Scholar 

  19. Nagalla, S. et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 117, 5189–5197 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ambros, V., Lee, R. C., Lavanway, A., Williams, P. T. & Jewell, D. MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr. Biol. 13, 807–818 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Carrington, J. C. & Ambros, V. Role of microRNAs in plant and animal development. Science 301, 336–338 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Ambros, V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113, 673–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ambros, V. MicroRNAs: tiny regulators with great potential. Cell 107, 823–826 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Ambros, V. MicroRNAs and developmental timing. Curr. Opin. Genet. Dev. 21, 511–517 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cloonan, N. Re-thinking miRNA-mRNA interactions: intertwining issues confound target discovery. Bioessays 37, 379–388 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Small, E. M. & Olson, E. N. Pervasive roles of microRNAs in cardiovascular biology. Nature 469, 336–342 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wahlgren, J. et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40, e130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Heijnen, H. F., Schiel, A. E., Fijnheer, R., Geuze, H. J. & Sixma, J. J. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94, 3791–3799 (1999).

    CAS  PubMed  Google Scholar 

  29. Small, E. M., Frost, R. J. A. & Olson, E. N. MicroRNAs add a new dimension to cardiovascular disease. Circulation 121, 1022–1032 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Hinkel, R., Ng, J. K. M. & Kupatt, C. Targeting microRNAs for cardiovascular therapeutics in coronary artery disease. Curr. Opin. Cardiol. 29, 586–594 (2014).

    Article  PubMed  Google Scholar 

  32. Dong, S. et al. MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J. Biol. Chem. 284, 29514–29525 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, R., Li, N., Zhang, Y., Ran, Y. & Pu, J. Circulating microRNAs are promising novel biomarkers of acute myocardial infarction. Intern. Med. 50, 1789–1795 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. McManus, D. D. & Ambros, V. Circulating MicroRNAs in cardiovascular disease. Circulation 124, 1908–1910 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  35. McManus, D. D. et al. Relations between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study. Heart Rhythm 11, 663–669 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. McManus, D. D. et al. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study). Heart Rhythm 12, 3–10 (2015).

    Article  PubMed  Google Scholar 

  37. Fichtlscherer, S. et al. Circulating microRNAs in patients with coronary artery disease. Circ. Res. 107, 677–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Freedman, J. E. et al. The distribution of circulating microRNA and their relation to coronary disease. F1000Res. 1, 50 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. De Rosa, S. et al. Transcoronary concentration gradients of circulating microRNAs. Circulation 124, 1936–1944 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Fichtlscherer, S., Zeiher, A. M. & Dimmeler, S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler. Thromb. Vasc. Biol. 31, 2383–2390 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Oliveira-Carvalho, V., da Silva, M. M. F., Guimarães, G. V., Bacal, F. & Bocchi, E. A. MicroRNAs: new players in heart failure. Mol. Biol. Rep. 40, 2663–2670 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Liebetrau, C. et al. Release kinetics of circulating muscle-enriched microRNAs in patients undergoing transcoronary ablation of septal hypertrophy. J. Am. Coll. Cardiol. 62, 992–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Das, S. & Halushka, M. K. Extracellular vesicle microRNA transfer in cardiovascular disease. Cardiovasc. Pathol. 24, 199–206 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Georgantas, R. W. et al. CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc. Natl Acad. Sci. USA 104, 2750–2755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barroga, C. F., Pham, H. & Kaushansky, K. Thrombopoietin regulates c-Myb expression by modulating micro RNA 150 expression. Exp. Hematol. 36, 1585–1592 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Opalinska, J. B. et al. MicroRNA expression in maturing murine megakaryocytes. Blood 116, e128–e138 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Labbaye, C. et al. A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat. Cell Biol. 10, 788–801 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Stratz, C. et al. Micro-array profiling exhibits remarkable intra-individual stability of human platelet micro-RNA. Thromb. Haemost. 107, 634–641 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Xu, X. et al. Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms. Blood 120, 3575–3585 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Plé, H. et al. The repertoire and features of human platelet microRNAs. PLoS ONE 7, e50746 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cecchetti, L. et al. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 118, 1903–1911 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Diehl, P. et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc. Res. 93, 633–644 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Freedman, J. E. et al. Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart study. Circulation 122, 119–129 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lood, C. et al. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116, 1951–1957 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Simon, L. M. et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 123, e37–e45 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jain, S. et al. Expression of regulatory platelet microRNAs in patients with sickle cell disease. PLoS ONE 8, e60932 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Healy, A. M. et al. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 113, 2278–2284 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Gidlöf, O. et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 121, 3908–3917 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Kahr, W. H. A. et al. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nat. Genet. 43, 738–740 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gnatenko, D. V. et al. Class prediction models of thrombocytosis using genetic biomarkers. Blood 115, 7–14 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Landry, P. et al. Existence of a microRNA pathway in anucleate platelets. Nat. Struct. Mol. Biol. 16, 961–966 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Willeit, P. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ. Res. 112, 595–600 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Kondkar, A. A. et al. VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J. Thromb. Haemost. 8, 369–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Gatsiou, A., Boeckel, J.-N., Randriamboavonjy, V. & Stellos, K. MicroRNAs in platelet biogenesis and function: implications in vascular homeostasis and inflammation. Curr. Vasc. Pharmacol. 10, 524–531 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Risitano, A., Beaulieu, L. M., Vitseva, O. & Freedman, J. E. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 119, 6288–6295 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aatonen, M., Grönholm, M. & Siljander, P. R.-M. Platelet-derived microvesicles: multitalented participants in intercellular communication. Semin. Thromb. Hemost. 38, 102–113 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Montecalvo, A. et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119, 756–766 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Laffont, B. et al. Activated platelets can deliver mRNA regulatory Ago2-microRNA complexes to endothelial cells via microparticles. Blood 122, 253–261 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Pan, Y. et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J. Immunol. 192, 437–446 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Ward, J. A. et al. Circulating cell and plasma microRNA profiles differ between non-ST-segment and ST-segment-elevation myocardial infarction. Fam. Med. Med. Sci. Res. 2, 108 (2013).

    PubMed  PubMed Central  Google Scholar 

  73. de Boer, H. C. et al. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur. Heart J. 34, 3451–3457 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Hunter, M. P. et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 3, e3694 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Italiano, J. E., Mairuhu, A. T. A. & Flaumenhaft, R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr. Opin. Hematol. 17, 578–584 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Cheng, H. H. et al. Plasma processing conditions substantially influence circulating microRNA biomarker levels. PLoS ONE 8, e64795 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zampetaki, A. et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J. Am. Coll. Cardiol. 60, 290–299 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Goren, Y. et al. Relation of reduced expression of miR-150 in platelets to atrial fibrillation in patients with chronic systolic heart failure. Am. J. Cardiol. 113, 976–981 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Tang, Y. et al. MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. Cardiovasc. Res. 106, 387–397 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hulsmans, M. & Holvoet, P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc. Res. 100, 7–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Zhang, Y.-Y. 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 38, 65–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Duisters, R. F. et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ. Res. 104, 170–178 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Karolina, D. S. et al. Circulating miRNA profiles in patients with metabolic syndrome. J. Clin. Endocrinol. Metab. 97, E2271–E2276 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, Y.-S., Zhou, J., Hong, K., Cheng, X.-S. & Li, Y.-G. MicroRNA-223 displays a protective role against cardiomyocyte hypertrophy by targeting cardiac troponin I-interacting kinase. Cell. Physiol. Biochem. 35, 1546–1556 (2015).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by grants UH2TR000921 and U01OD019771 (J.E.F.) from the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director, and KL2RR031981 (D.D.M.) from the University of Massachusetts Medical School's Center for Clinical and Translational Science Award.

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  1. Cardiology Division, Department of Medicine, University of Massachusetts Medical School, AS7-1051, 368 Plantation Street, Worcester, 01605-4319, MA, USA

    David D. McManus & Jane E. Freedman

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Both authors researched data for the article, discussed its content, and wrote, reviewed, and edited the manuscript before submission.

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Correspondence to Jane E. Freedman.

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McManus, D., Freedman, J. MicroRNAs in platelet function and cardiovascular disease. Nat Rev Cardiol 12, 711–717 (2015). https://doi.org/10.1038/nrcardio.2015.101

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