MicroRNAs in platelet physiology and pathology

Summary

MicroRNAs (miRNAs), highly conserved, short (approx. 22 nucleotides) non-coding RNAs, exhibit a fine-tune control over gene expression by complementary sequence binding and translational repression of protein coding mRNA transcripts. Recently, the role of miRNAs has been increasingly investigated in various physiological or pathophysiological events.

Circulating platelets are crucial for coagulation physiology to maintain haemostatic balance and are involved in various pathologies such as atherosclerosis and thrombosis. Anucleate platelets lack genomic DNA but inherit diverse array of functional coding or non-coding RNAs and translational machinery from their parent cells – mega-karyocytes enabling activated platelets to synthesize proteins which suggests the possibility of post transcriptional gene regulation in platelets. Expression of functionally active miRNAs in platelets changes during platelet activation indicating a role in platelet biology.

Here, we present a review on recently identified platelet miRNAs and their role in platelet physiology that is essential for maintaining haemostasis.

Zusammenfassung

MicroRNAs (miRNAs) sind evolutionär hochkonservierte kurze (etwa 20 Nukleotide) nicht kodierende RNA Moleküle, die eine Kontrolle der Genexpression durch Bindung an komplementäre mRNA-Sequenzen und translationale Repression von Proteinkodierenden mRNA-Transkripten bewirken. MiRNAs sind an vielen physiologischen und pathophysiologischen Vorgängen des Körpers beteiligt.

Zirkulierende Thrombozyten sind essenziell für die Balance der Blutgerinnung und auch bedeutend für die vaskuläre Integrität. Sie sind ebenso bei atherosklerotischen wie auch bei thrombotischen Erkrankungen involviert. Anuklären Thrombozyten fehlt genomische DNA, aber sie besitzen eine Anzahl funktionell kodierender aber auch nicht kodierender RNA-Moleküle. Des Weiteren besitzen Thrombozyten eine funktionstüchtige translationale Maschinerie, die es ihnen erlaubt, Proteine zu synthetisieren – Prozesse, die wiederum über miRNAs reguliert werden.

Die Bedeutung von nicht kodierenden micro-RNAs in der Regulation der Thrombozytenfunktion ist daher Gegenstand dieses Übersichtsartikels.

Keywords

MicroRNAs

Schlüsselwörter

MicroRNAs

• References

• 1 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-297.
• 2 Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993; 75: 855-862.
• 3 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: 843-854.
• 4 Thum T, Galuppo P, Wolf C. et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 2007; 116: 258-267.
• 5 Fiedler J, Jazbutyte V, Kirchmaier BC. et al. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation 2011; 124: 720-730.
• 6 Thum T, Gross C, Fiedler J. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008; 456: 980-984.
• 7 Ucar A, Gupta SK, Fiedler J. et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nature communications 2012; 03: 1078.
• 8 Chen C, Ridzon DA, Broomer AJ. et al. Real-time quantification of microRNAs by stem-loop RTPCR. Nucleic Acids Res 2005; 33: e179.
• 9 Dangwal S, Bang C, Thum T. Novel techniques and targets in cardiovascular microRNA research. Cardiovascular Res 2012; 93: 545-554.
• 10 Ho-Tin-Noe B, Demers M, Wagner DD. How platelets safeguard vascular integrity. J Thromb Haemost 2011; 09 (Suppl. 01) 56-65.
• 11 Broos K, Feys HB, De Meyer SF. et al. Platelets at work in primary hemostasis. Blood Rev 2011; 25: 155-167.
• 12 Kottke-Marchant K. Importance of platelets and platelet response in acute coronary syndromes. Cleveland Clin J Med 2009; 76 (Suppl. 01) S2-S7.
• 13 Boilard E, Nigrovic PA, Larabee K. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
• 14 Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 (Suppl. 01) S13-S33.
• 15 Jain S, Harris J, Ware J. Platelets: linking hemostasis and cancer. Arterioscler Thromb Vasc Biol 2010; 30: 2362-2367.
• 16 Avecilla ST, Hattori K, Heissig B. et al. Chemokinemediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 2004; 10: 64-71.
• 17 Patel SR, Hartwig JH, IJ Jr E. The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 2005; 115: 3348-3354.
• 18 Denis MM, Tolley ND, Bunting M. et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 2005; 122: 379-391.
• 19 Weyrich AS, Schwertz H, Kraiss LW, Zimmerman GA. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 07: 241-246.
• 20 Thon JN, Devine DV. Translation of glycoprotein IIIa in stored blood platelets. Transfusion 2007; 47: 2260-2270.
• 21 Landry P, Plante I, Ouellet DL. et al. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16: 961-966 #
• 22 Dittrich M, Birschmann I, Pfrang J. et al. Analysis of SAGE data in human platelets: features of the transcriptome in an anucleate cell. Thromb Haemost 2006; 95: 643-651.
• 23 Bauersachs J, Thum T. Biogenesis and regulation of cardiovascular micro-RNAs. Circ Res 2011; 109: 334-347.
• 24 Lee Y, Ahn C, Han J. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425: 415-419.
• 25 Gregory RI, Yan KP, Amuthan G. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432: 235-240.
• 26 Chendrimada TP, Gregory RI, Kumaraswamy E. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005; 436: 740-744.
• 27 Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011; 469: 336-342.
• 28 Shyu AB, Wilkinson MF, van Hoof A. Messenger RNA regulation: to translate or to degrade. EMBO J 2008; 27: 471-481.
• 29 Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010; 466: 835-840.
• 30 Ple H, Landry P, Benham A. et al. The repertoire and features of human platelet microRNAs. PLoS One 2012; 07: e50746.
• 31 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
• 32 Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113: 340-345.
• 33 Hechler B, Gachet C. P2 receptors and platelet function. Purinergic Signal 2011; 07: 293-303.
• 34 Diehl P, Fricke A, Sander L. et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93: 633-644.
• 35 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; 08: 369-378.
• 36 Nagalla S, Shaw C, Kong X. et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 2011; 117: 5189-5197.
• 37 Osman A, Falker K. Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes. Platelets 2011; 22: 433-441.
• 38 Reid JG, Nagaraja AK, Lynn FC. et al. Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5’-seed/ cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes. Genome Res 2008; 18: 1571-1581.
• 39 Zampetaki A, Mayr M. MicroRNAs in vascular and metabolic disease. Circ Res 2012; 110: 508-522.
• 40 Rautou PE, Vion AC, Amabile N. et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593-606.
• 41 Sondermeijer BM, Bakker A, Halliani A. et al. Platelets in patients with premature coronary artery disease exhibit upregulation of miRNA340* and miRNA624*. PloS one 2010; 06: e25946.
• 42 Girardot M, Pecquet C, Boukour S. et al. miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. Blood 2010; 116: 437-445.
• 43 Dangwal S, Thum T. MicroRNAs in platelet biogenesis and function. Thromb Haemost 2012; 108: 599-604.