Page 217 - Haematologica Vol. 107 - September 2022

ARTICLE - Effects of specific inhibition of platelet MRP4
R. Wolf et al.
Acknowledgments
The authors thank Edita Kaliwe and Sarah Polster for their expert technical assistance. Mrp4-deficient (Mrp4 (-/-)) mice were kindly provided by the late Dr. Gary D. Kruh, Cancer Center, University of Illinois, Chicago, USA.
Funding
This study was supported by grants from the Deutsche For- schungsgemeinschaft to GJ (DFG, JE 234/4-1) and to BHR (DFG, RA 1714/1-2). RW has received a doctoral scholarship
References
1. Jedlitschky G, Tirschmann K, Lubenow LE, et al. The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage. Blood. 2004;104(12):3603-3610.
2. Niessen J, Jedlitschky G, Grube M, et al. Expression of ABC-type transport proteins in human platelets. Pharmacogenet Genomics. 2010;20(6):396-400.
3. Mattiello T, Guerriero R, Lotti LV, et al. Aspirin extrusion from human platelets through multidrug resistance protein-4- mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. J Am Coll Cardiol. 2011;58(7):752-761.
4. Azouzi S, Mikdar M, Hermand P, et al. Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation. Blood. 2020; 6;135(6):441-448.
5. Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, et al. Cellular export of drugs and signaling molecules by the ATP- binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug Metab Rev. 2005;37(1):253-278.
6. Jedlitschky G, Greinacher A, Kroemer HK. Transporters in human platelets: physiologic function and impact for pharmacotherapy. Blood. 2012;119(15):3394-3402.
7. Sassi Y, Lipskaia L, Vandecasteele G, et al. Multidrug resistance- associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. J Clin Invest. 2008;118(8):2747-2757.
8. Coepsel S, Garcia C, Diez F, et al. Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem. 2011;286(9):6979-698.
9. Decouture B, Dreano E, Belleville-Rolland T, et al. Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice. Blood. 2015;126(15):1823-1830.
10. Cheepala SB, Pitre A, Fukuda Y, et al. The ABCC4 membrane transporter modulates platelet aggregation. Blood. 2015;126(20):2307-2319.
11. Belleville-Rolland T, Sassi Y, Decouture B, et al. MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. Pharmacol Res. 2016;107:381-389.
12. Reid G, Wielinga P, Zelcer N, et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003;100(16):9244-9249.
13. Rius M, Hummel-Eisenbeiss J, Keppler D. ATP-dependent transport of leukotrienes B4 and C4 by the multidrug resistance protein ABCC4 (MRP4). J Pharmacol Exp Ther. 2008;324(1):86-94.
from the DZHK (Deutsches Zentrum für Herz-Kreislauf-For- schung e.V., grant 81X3400103). RP and AG receive support from Deutsche Forschungsgemeinschaft, grant/award number: 374031971-TRR 240. We also acknowledge support for the Article Processing Charge from the DFG and the Open Access Publication Fund of the University of Greifswald.
Data-sharing statement
All original data and protocols can be made available to other investigators upon request.
14. Vogt K, Mahajan-Thakur S, Wolf R, et al. Release of platelet- derived sphingosine-1-phosphate involves multidrug resistance protein 4 (MRP4/ABCC4) and is inhibited by statins. Thromb Haemost. 2018;118(1):132-142.
15. Massimi I, Lotti LV, Temperilli F, et al. Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment. Thromb Haemost. 2016;116(6):1100-1110.
16. Alemanno L, Massimi I, Klaus V et al. Impact of multidrug resistance protein-4 inhibitors on modulating platelet function and high on-aspirin treatment platelet reactivity. Thromb Haemost. 2018;118(3):490-501.
17. Marcantoni E, Allen N, Cambria MR, et al. Platelet transcriptome profiling in HIV and ATP-binding cassette subfamily C member 4 (ABCC4) as a mediator of platelet activity. JACC Basic Transl Sci 2018;3(1):9-22.
18. Keppler D, Jedlitschky G, Leier I. Transport function and substrate specificity of multidrug resistance protein. Methods Enzymol. 1998;292:607-616.
19. Borgognone A, Pulcinelli FM. Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport. Thromb Haemost. 2012;108(5):955-962.
20. Lien LM, Chen ZC, Chung CL, et al. Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo. Eur J Pharmacol. 2014;737:159-167.
21. Cheung L, Flemming CL, Watt F, et al. High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Biochem Pharmacol. 2014; 91(1):97-108.
22. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671-675.
23. Jahn K, Handtke S, Palankar R, et al. Pneumolysin induces platelet destruction, not platelet activation, which can be prevented by immunoglobulin preparations in vitro. Blood Adv. 2020;4(24):6315-6326.
24. Mangin PH, Gardiner EE, Nesbitt WS, et al. In vitro flow based systems to study platelet function and thrombus formation: recommendations for standardization: communication from the SSC on Biorheology of the ISTH. J Thromb Haemost. 2020;18(3):748-752.
25. Schrör K, Rauch BH. Aspirin and lipid mediators in the cardiovascular system. Prostaglandins Other Lipid Mediat. 2015;121(Pt A):17-23.
26. Tamargo J, Duarte J, Caballero R, Delpón E. Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure. Curr Opin Investig Drugs. 2010;11(9):1039-1047.
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