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Thromb Haemost 2019; 119(09): 1451-1460
DOI: 10.1055/s-0039-1692681
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

Wen Wen Liu
1   Department of Geriatrics, Peking University First Hospital, Xicheng District, Beijing, China
,
Hao Wang
1   Department of Geriatrics, Peking University First Hospital, Xicheng District, Beijing, China
,
Xia Huan Chen
1   Department of Geriatrics, Peking University First Hospital, Xicheng District, Beijing, China
,
Sidney W. Fu
2   Division of Genomic Medicine, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
,
Mei Lin Liu
1   Department of Geriatrics, Peking University First Hospital, Xicheng District, Beijing, China
› Author Affiliations Funding This study was supported by the International Science & Technology Cooperation Project of China (2013DFA30860). The funding source was the government agency, which played no role in the collection, analysis, and interpretation of data or the preparation of the manuscript.
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Publication History

15 January 2019

07 May 2019

Publication Date:
02 July 2019 (online)

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Abstract

Aspirin has been widely used for the prevention of cardiovascular diseases, but its antiplatelet efficiency varies between individuals. The present study aimed to evaluate response to aspirin based on gene profiles as well as potential regulating pathways using human blood samples and cell lines. Platelet function in patients 50 years or older with coronary artery disease on 100 mg/day aspirin was measured by light transmission aggregometry (LTA) of arachidonic acid (AA)-induced platelet aggregation. The expression of eight candidate genes—PTGS1/COX1, PLA2G4A, PLA2G6, PLA2G7, TBXAS1, TBXA2R, PTGIR, and ITGA2B—and the ingredients involved in AA metabolism were analyzed. Our data showed that the expressions of thromboxane A synthase 1 (TBXAS1), thromboxane synthase (TXS), and thromboxane B2 (TXB2) were increased in the upper quartile of platelet aggregation (LTA-AA_Q4) group compared with the lower quartile of platelet aggregation (LTA-AA_Q1) group. Our bioinformatics analysis suggested that TBXAS1 was targeted by miR-34b-3p via binding to its 3′-UTR, which was subsequently verified experimentally. Although overexpression of miR-34b-3p exhibited no apparent effect on cell proliferation, inhibition of miR-34b-3p promoted megakaryocyte viability. Our data demonstrated that the expression of TBXAS1 was higher in the aspirin hyporesponsiveness group than that in the hyperresponsiveness group, suggesting that high expression of TBXAS1 may be associated with aspirin hyporesponsiveness. miR-34b-3p may regulate the platelet and aspirin response by suppressing TBXAS1 expression and megakaryocyte proliferation.

Keywords

aspirin efficiency - thromboxane synthase - miR-34b-3p - megakaryocyte - coronary artery disease

Authors' Contributions

WW.L developed an overall research plan, collected samples together with clinical data, performed experiments, and wrote the paper; H.W. assisted with the experiments of protein extraction and Western blot assays; XH.C provided essential medical records; SW.F interpreted the data and revised the manuscript; ML.L directed the overall project, interpreted the data, and revised the manuscript.


Supplementary Material

 

  • References

  • 1 Olechowski B, Ashby A, Mariathas M, Khanna V, Mahmoudi M, Curzen N. Is arachidonic acid stimulation really a test for the response to aspirin? Time to think again?. Expert Rev Cardiovasc Ther 2017; 15 (01) 35-46
    CrossrefPubMedSearch in Google Scholar
  • 2 Kasmeridis C, Apostolakis S, Lip GY. Aspirin and aspirin resistance in coronary artery disease. Curr Opin Pharmacol 2013; 13 (02) 242-250
    CrossrefPubMedSearch in Google Scholar
  • 3 Kuliczkowski W, Witkowski A, Polonski L. , et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009; 30 (04) 426-435
    PubMedSearch in Google Scholar
  • 4 Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28 (14) 1702-1708
    CrossrefPubMedSearch in Google Scholar
  • 5 Hamberg M, Svensson J, Samuelsson B. Letter: mechanism of the anti-aggregating effect of aspirin on human platelets. Lancet 1974; 2 (7874): 223-224
    PubMedSearch in Google Scholar
  • 6 Baothman BK, Smith J, Kay LJ, Suvarna SK, Peachell PT. Prostaglandin D2 generation from human lung mast cells is catalysed exclusively by cyclooxygenase-1. Eur J Pharmacol 2018; 819: 225-232
    CrossrefPubMedSearch in Google Scholar
  • 7 Slatter DA, Aldrovandi M, O'Connor A. , et al. Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metab 2016; 23 (05) 930-944
    CrossrefPubMedSearch in Google Scholar
  • 8 Ozes B, Karagoz N, Schüle R. , et al. PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clin Genet 2017; 92 (05) 534-539
    CrossrefPubMedSearch in Google Scholar
  • 9 Chi Y, Shi C, Zhang X, Xi Y. Interaction between nonsynonymous polymorphisms in PLA2G7 gene and smoking on the risk of coronary heart disease in a Chinese population. J Thromb Thrombolysis 2018; 46 (01) 125-130
    CrossrefPubMedSearch in Google Scholar
  • 10 Amano H, Nakamura M, Ito Y. , et al. Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia. J Surg Res 2016; 204 (01) 153-163
    CrossrefPubMedSearch in Google Scholar
  • 11 Mesitskaya DF, Syrkin AL, Aksenova MG, Zhang Y, Zamyatnin Jr AA, Kopylov PY. Thromboxane A synthase: a new target for the treatment of cardiovascular diseases. Cardiovasc Hematol Agents Med Chem 2018; 16 (02) 81-87
    PubMedSearch in Google Scholar
  • 12 Li L, He ZY, Wang YZ, Liu X, Yuan LY. Associations between thromboxane A synthase 1 gene polymorphisms and the risk of ischemic stroke in a Chinese Han population. Neural Regen Res 2018; 13 (03) 463-469
    CrossrefPubMedSearch in Google Scholar
  • 13 Mumford AD, Nisar S, Darnige L. , et al; UK GAPP Study Group. Platelet dysfunction associated with the novel Trp29Cys thromboxane A2 receptor variant. J Thromb Haemost 2013; 11 (03) 547-554
    CrossrefPubMedSearch in Google Scholar
  • 14 Pillois X, Peters P, Segers K, Nurden AT. In silico analysis of structural modifications in and around the integrin αIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia. Mol Genet Genomic Med 2018; 6 (02) 249-260
    CrossrefPubMedSearch in Google Scholar
  • 15 Shimizu M, Yoshimura S, Takizawa S, Kohara S, Inoko H, Takagi S. Effect of single nucleotide polymorphisms of the prostacyclin receptor gene on platelet activation in Japanese healthy subjects and patients with cerebral infarction. J Clin Neurosci 2013; 20 (06) 851-856
    CrossrefPubMedSearch in Google Scholar
  • 16 Edelstein LC, Bray PF. MicroRNAs in platelet production and activation. Blood 2011; 117 (20) 5289-5296
    CrossrefPubMedSearch in Google Scholar
  • 17 McDonald AC, Vira M, Shen J. , et al. Circulating microRNAs in plasma as potential biomarkers for the early detection of prostate cancer. Prostate 2018; 78 (06) 411-418
    CrossrefPubMedSearch in Google Scholar
  • 18 Mizuno K, Mataki H, Arai T. , et al. The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. J Hum Genet 2017; 62 (07) 671-678
    CrossrefPubMedSearch in Google Scholar
  • 19 Huang RY, Li MY, Ng CS. , et al. Thromboxane A2 receptor α promotes tumor growth through an autoregulatory feedback pathway. J Mol Cell Biol 2013; 5 (06) 380-390
    CrossrefPubMedSearch in Google Scholar
  • 20 Wang JW, Chen P, Qian XK. , et al. [miR-34b-3p regulates the angiogenesis of senescent endothelial cell]. Zhonghua Yi Xue Za Zhi 2016; 96 (16) 1293-1297
    PubMedSearch in Google Scholar
  • 21 Singh AK, Rooge SB, Varshney A. , et al. Global microRNA expression profiling in the liver biopsies of hepatitis B virus-infected patients suggests specific microRNA signatures for viral persistence and hepatocellular injury. Hepatology 2018; 67 (05) 1695-1709
    CrossrefPubMedSearch in Google Scholar
  • 22 Zhao L, Wu S, Huang E, Gnatenko D, Bahou WF, Zhu W. Integrated micro/messenger RNA regulatory networks in essential thrombocytosis. PLoS One 2018; 13 (02) e0191932
    CrossrefPubMedSearch in Google Scholar
  • 23 Verdoia M, Pergolini P, Rolla R. , et al. Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. J Thromb Haemost 2016; 14 (01) 57-64
    CrossrefPubMedSearch in Google Scholar
  • 24 Breet NJ, van Donkersgoed HE, van Werkum JW. , et al. Is platelet inhibition due to thienopyridines increased in elderly patients, in patients with previous stroke and patients with low body weight as a possible explanation of an increased bleeding risk?. Neth Heart J 2011; 19 (06) 279-284
    CrossrefPubMedSearch in Google Scholar
  • 25 Zhang JW, Liu WW, McCaffrey TA. , et al. Predictors of high on-aspirin platelet reactivity in elderly patients with coronary artery disease. Clin Interv Aging 2017; 12: 1271-1279
    CrossrefPubMedSearch in Google Scholar
  • 26 Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004; 110 (19) e489 –e493
    CrossrefPubMedSearch in Google Scholar
  • 27 Liu T, Zhang J, Chen X. , et al. Comparison between urinary 11-dehydrothromboxane B2 detection and platelet light transmission aggregometry (LTA) assays for evaluating aspirin response in elderly patients with coronary artery disease. Gene 2015; 571 (01) 23-27
    CrossrefPubMedSearch in Google Scholar
  • 28 Fontana P, Zufferey A, Daali Y, Reny JL. Antiplatelet therapy: targeting the TxA2 pathway. J Cardiovasc Transl Res 2014; 7 (01) 29-38
    CrossrefPubMedSearch in Google Scholar
  • 29 Oh SH, Kim YH, Park SM. , et al. Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients. Pharmacogenomics 2011; 12 (03) 351-363
    CrossrefPubMedSearch in Google Scholar
  • 30 An GH, Sim SY, Jwa CS, Kim GH, Lee JY, Kang JK. Thromboxane A2 synthetase inhibitor plus low dose aspirin : can it be a salvage treatment in acute stroke beyond thrombolytic time window. J Korean Neurosurg Soc 2011; 50 (01) 1-5
    CrossrefPubMedSearch in Google Scholar
  • 31 Lev PR, Goette NP, Glembotsky AC. , et al. Production of functional platelet-like particles by the megakaryoblastic DAMI cell line provides a model for platelet biogenesis. Platelets 2011; 22 (01) 28-38
    PubMedSearch in Google Scholar
  • 32 Tozawa K, Ono-Uruga Y, Yazawa M. , et al. Megakaryocytes and platelets from a novel human adipose-derived mesenchymal stem cell line. Blood 2018; 133 (07) 633-643
    PubMedSearch in Google Scholar
  • 33 Temperilli F, Di Franco M, Massimi I. , et al. Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and multidrug resistance protein 4 expression in human platelets. Vascul Pharmacol 2016; 76: 11-17
    CrossrefPubMedSearch in Google Scholar
  • 34 Voora D, Rao AK, Jalagadugula GS. , et al. Systems pharmacogenomics finds RUNX1 is an aspirin-responsive transcription factor linked to cardiovascular disease and colon cancer. EBioMedicine 2016; 11: 157-164
    CrossrefPubMedSearch in Google Scholar
  • 35 Micklewright JJ, Layhadi JA, Fountain SJ. P2Y12 receptor modulation of ADP-evoked intracellular Ca2+ signalling in THP-1 human monocytic cells. Br J Pharmacol 2018; 175 (12) 2483-2491
    CrossrefPubMedSearch in Google Scholar
  • 36 Becher T, Schulze TJ, Schmitt M. , et al. Ezetimibe inhibits platelet activation and uPAR expression on endothelial cells. Int J Cardiol 2017; 227: 858-862
    CrossrefPubMedSearch in Google Scholar
  • 37 Biswas I, Panicker SR, Cai X, Mehta-D'souza P, Rezaie AR. Inorganic polyphosphate amplifies high mobility group Box 1-mediated Von Willebrand factor release and platelet string formation on endothelial cells. Arterioscler Thromb Vasc Biol 2018; 38 (08) 1868-1877
    CrossrefPubMedSearch in Google Scholar
  • 38 Kaudewitz D, Skroblin P, Bender LH. , et al. Association of microRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
    CrossrefPubMedSearch in Google Scholar
  • 39 Sunderland N, Skroblin P, Barwari T. , et al. MicroRNA biomarkers and platelet reactivity: the clot thickens. Circ Res 2017; 120 (02) 418-435
    CrossrefPubMedSearch in Google Scholar
  • 40 Carobbio A, Thiele J, Passamonti F. , et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011; 117 (22) 5857-5859
    CrossrefPubMedSearch in Google Scholar
  • 41 Finazzi G, Vannucchi AM, Barbui T. Prefibrotic myelofibrosis: treatment algorithm 2018. Blood Cancer J 2018; 8 (11) 104
    CrossrefPubMedSearch in Google Scholar
  • 42 Ebert MS, Sharp PA. Emerging roles for natural microRNA sponges. Curr Biol 2010; 20 (19) R858-R861
    CrossrefPubMedSearch in Google Scholar