Multidrug Resistance Protein 4 (MRP4/ABCC4): A Suspected Efflux Transporter for Human’s Platelet Activation

Author(s): Ioannis Angelis*, Vassilios Moussis, Demokritos C. Tsoukatos, Vassilios Tsikaris

Journal Name: Protein & Peptide Letters

Volume 28 , Issue 9 , 2021

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Graphical Abstract:


The main role of platelets is to contribute to hemostasis. However, under pathophysiological conditions, platelet activation may lead to thrombotic events of cardiovascular diseases. Thus, anti-thrombotic treatment is important in patients with cardiovascular disease. This review focuses on a platelet receptor, a transmembrane protein, the Multidrug Resistance Protein 4, MRP4, which contributes to platelet activation, by extruding endogenous molecules responsible for their activation and accumulation. The regulation of the intracellular concentration levels of these molecules by MRP4 turned to make the protein suspicious and at the same time an interesting regulatory factor of platelet normal function. Especially, the possible role of MRP4 in the excretion of xenobiotic and antiplatelet drugs such as aspirin is discussed, thus imparting platelet aspirin tolerance and correlating the protein with the ineffectiveness of aspirin antiplatelet therapy. Based on the above, this review finally underlines that the development of a highly selective and targeted strategy for platelet MRP4 inhibition will also lead to inhibition of platelet activation and accumulation.

Keywords: MRP4/ABCC4, platelet, cAMP-compartmentalization, aspirin, antiplatelet target, Multidrug Resistance (MDR).

Lage, H. ABC-transporters: implications on drug resistance from microorganisms to human cancers. Int. J. Antimicrob. Agents, 2003, 22(3), 188-199.[] [PMID: 13678820]
Jones, P.M.; George, A.M. The ABC transporter structure and mechanism: perspectives on recent research. Cell. Mol. Life Sci., 2004, 61(6), 682-699.[] [PMID: 15052411]
Chen, Z-S.; Tiwari, A.K. Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J., 2011, 278(18), 3226-3245.[] [PMID: 21740521]
Slot, A.J.; Molinski, S.V.; Cole, S.P.C. Mammalian multidrug-resistance proteins (MRPs). Essays Biochem., 2011, 50(1), 179-207.[PMID: 21967058]
Rees, D.C.; Johnson, E.; Lewinson, O. ABC transporters: the power to change. Nat. Rev. Mol. Cell Biol., 2009, 10(3), 218-227.[] [PMID: 19234479]
Borst, P.; Evers, R.; Kool, M.; Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst., 2000, 92(16), 1295-1302.[] [PMID: 10944550]
Tagami, M.; Kusuhara, S.; Honda, S.; Tsukahara, Y.; Negi, A. Expression of ATP-binding cassette transporters at the inner blood-retinal barrier in a neonatal mouse model of oxygen-induced retinopathy. Brain Res., 2009, 1283, 186-193.[] [PMID: 19505448]
Allikmets, R.; Gerrard, B.; Hutchinson, A.; Dean, M. Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum. Mol. Genet., 1996, 5(10), 1649-1655.[] [PMID: 8894702]
Kool, M.; de Haas, M.; Scheffer, G.L.; Scheper, R.J.; van Eijk, M.J.T.; Juijn, J.A.; Baas, F.; Borst, P. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res., 1997, 57(16), 3537-3547.[PMID: 9270026]
Lee, K.; Belinsky, M.G.; Bell, D.W.; Testa, J.R.; Kruh, G.D. Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res., 1998, 58(13), 2741-2747.[PMID: 9661885]
Wielinga, P.R.; van der Heijden, I.; Reid, G.; Beijnen, J.H.; Wijnholds, J.; Borst, P. Characterization of the MRP4- and MRP5-mediated transport of cyclic nucleotides from intact cells. J. Biol. Chem., 2003, 278(20), 17664-17671.[] [PMID: 12637526]
Jorajuria, S.; Dereuddre-Bosquet, N.; Naissant-Storck, K.; Dormont, D.; Clayette, P. Differential expression levels of MRP1, MRP4, and MRP5 in response to human immunodeficiency virus infection in human macrophages. Antimicrob. Agents Chemother., 2004, 48(5), 1889-1891.[] [PMID: 15105153]
Maciejewska, K.; Parczewski, M. ABCC protein function and genetic variability in HIV infection. HIV AIDS Rev., 2014, 13(3), 63-67.[]
Copsel, S.; Bruzzone, A.; May, M.; Beyrath, J.; Wargon, V.; Cany, J.; Russel, F.G.M.; Shayo, C.; Davio, C. Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia. Oncotarget, 2014, 5(19), 9308-9321.[] [PMID: 25301721]
Zhou, S.F.; Wang, L.L.; Di, Y.M.; Xue, C.C.; Duan, W.; Li, C.G.; Li, Y. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr. Med. Chem., 2008, 15(20), 1981-2039.[] [PMID: 18691054]
Wen, J.; Luo, J.; Huang, W.; Tang, J.; Zhou, H.; Zhang, W. The pharmacological and physiological role of multidrug-resistant protein 4. J. Pharmacol. Exp. Ther., 2015, 354(3), 358-375.[] [PMID: 26148856]
Marcantoni, E.; Allen, N.; Cambria, M.R.; Dann, R.; Cammer, M.; Lhakhang, T.; O’Brien, M.P.; Kim, B.; Worgall, T.; Heguy, A.; Tsirigos, A.; Berger, J.S. 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.[] [PMID: 30062189]
Pyrkov, T.V.; Kosinsky, Y.A.; Arseniev, A.S.; Priestle, J.P.; Jacoby, E.; Efremov, R.G. Docking of ATP to Ca-ATPase: considering protein domain motions. J. Chem. Inf. Model., 2007, 47(3), 1171-1181.[] [PMID: 17489554]
Zaitseva, J.; Jenewein, S.; Jumpertz, T.; Holland, I.B.; Schmitt, L. H662 is the linchpin of ATP hydrolysis in the nucleotide-binding domain of the ABC transporter HlyB. EMBO J., 2005, 24(11), 1901-1910.[] [PMID: 15889153]
El-Sheikh, A.A.K.; van den Heuvel, J.J.M.W.; Krieger, E.; Russel, F.G.M.; Koenderink, J.B. Functional role of arginine 375 in transmembrane helix 6 of multidrug resistance protein 4 (MRP4/ABCC4). Mol. Pharmacol., 2008, 74(4), 964-971.[] [PMID: 18612080]
Wittgen, H.G.M.; van den Heuvel, J.J.M.W.; Krieger, E.; Schaftenaar, G.; Russel, F.G.M.; Koenderink, J.B. Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity. Biochem. Pharmacol., 2012, 84(3), 366-373.[] [PMID: 22542979]
Chantemargue, B.; Di Meo, F.; Berka, K.; Picard, N.; Arnion, H.; Essig, M.; Marquet, P.; Otyepka, M.; Trouillas, P. Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms. Pharmacol. Res., 2018, 133, 318-327.[] [PMID: 29530601]
Berthier, J.; Arnion, H.; Saint-Marcoux, F.; Picard, N. Multidrug resistance-associated protein 4 in pharmacology: overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics. Life Sci., 2019, 231(June), 116540.[] [PMID: 31176778]
Chen, Y.; Yuan, X.; Xiao, Z.; Jin, H.; Zhang, L.; Liu, Z. Discovery of novel multidrug resistance protein 4 (MRP4) inhibitors as active agents reducing resistance to anticancer drug 6-Mercaptopurine (6-MP) by structure and ligand-based virtual screening. PLoS One, 2018, 13(10), e0205175.[] [PMID: 30321196]
Jedlitschky, G.; Tirschmann, K.; Lubenow, L.E.; Nieuwenhuis, H.K.; Akkerman, J.W.N.; Greinacher, A.; Kroemer, H.K. 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.[] [PMID: 15297306]
Jedlitschky, G.; Cattaneo, M.; Lubenow, L.E.; Rosskopf, D.; Lecchi, A.; Artoni, A.; Motta, G.; Niessen, J.; Kroemer, H.K.; Greinacher, A.; Elena, R. Role of MRP4 (ABCC4) in platelet adenine nucleotide-storage: evidence from patients with delta-storage pool deficiencies. Am. J. Pathol., 2010, 176(3), 1097-1103.[] [PMID: 20133816]
Mattiello, T.; Guerriero, R.; Lotti, L. Aspirin extrusion from human platelets through multidrug resistance protein-4 – mediated transport patients after coronary artery bypass grafting. J. Am. Coll. Cardiol., 2011, 58(7), 752-761.[] [PMID: 21816313]
Rius, M.; Hummel-eisenbeiss, J.; Keppler, D. ATP-dependent transport of leukotrienes B 4 and C 4 by the multidrug resistance protein ABCC4 (MRP4). J. Pharmacol. Exp. Ther., 2008, 324(1), 86-94.[]
Cheepala, S.B.; Pitre, A.; Fukuda, Y.; Takenaka, K.; Zhang, Y.; Wang, Y.; Frase, S.; Pestina, T.; Gartner, T.K.; Jackson, C.; Schuetz, J.D. The ABCC4 membrane transporter modulates platelet aggregation. Blood, 2015, 126(20), 2307-2319.[] [PMID: 26405223]
Hou, Y.; Carrim, N.; Wang, Y.; Gallant, R.C.; Marshall, A.; Ni, H. Platelets in hemostasis and thrombosis: novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J. Biomed. Res., 2015, 29(6), 437-444.[PMID: 26541706]
Leroy, J.; Vandecasteele, G.; Fischmeister, R. Cyclic AMP signaling in cardiac myocytes. Curr. Opin. Physiol., 2018, 1, 161-171.[]
Noé, L.; Peeters, K.; Izzi, B.; Van Geet, C.; Freson, K. Regulators of platelet cAMP levels: clinical and therapeutic implications. Curr. Med. Chem., 2010, 17(26), 2897-2905.[] [PMID: 20858171]
Midgett, C.; Stitham, J.; Martin, K.; Hwa, J. Prostacyclin receptor regulation from transcription to trafficking. Curr. Mol. Med., 2011, 11(7), 517-528.[] [PMID: 21707517]
Sim, D.S.; Merrill-Skoloff, G.; Furie, B.C.; Furie, B.; Flaumenhaft, R. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Blood, 2004, 103(6), 2127-2134.[] [PMID: 14645013]
Burkhart, J.M.; Vaudel, M.; Gambaryan, S.; Radau, S.; Walter, U.; Martens, L.; Geiger, J.; Sickmann, A.; Zahedi, R.P. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood, 2012, 120(15), e73-e82.[] [PMID: 22869793]
Dostmann, W.R.G.; Taylor, S.S. Identifying the molecular switches that determine whether (Rp)-cAMPS functions as an antagonist or an agonist in the activation of cAMP-dependent protein kinase I. Biochemistry, 1991, 30(35), 8710-8716.[] [PMID: 1653606]
Esseltine, J.L.; Scott, J.D. AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends Pharmacol. Sci., 2013, 34(12), 648-655.[] [PMID: 24239028]
Walter, U.; Gambaryan, S. cGMP and cGMP-dependent protein kinase in platelets and blood cells. Handb. Exp. Pharmacol., 2009, 191(191), 533-548.[] [PMID: 19089344]
Dorahy, D.J.; Lincz, L.F.; Meldrum, C.J.; Burns, G.F. Biochemical isolation of a membrane microdomain from resting platelets highly enriched in the plasma membrane glycoprotein CD36. Biochem. J., 1996, 319(Pt 1), 67-72.[] [PMID: 8870650]
Waldmann, R.; Nieberding, M.; WALTER, U. Vasodilator‐stimulated protein phosphorylation in platelets is mediated by CAMP‐ and CGMP‐dependent protein kinases. Eur. J. Biochem., 1987, 167(3), 441-448.[] [PMID: 2820726]
Aburima, A.; Wraith, K.S.; Raslan, Z.; Law, R.; Magwenzi, S.; Naseem, K.M. cAMP signaling regulates platelet myosin light chain (MLC) phosphorylation and shape change through targeting the RhoA-Rho kinase-MLC phosphatase signaling pathway. Blood, 2013, 122(20), 3533-3545.[] [PMID: 24100445]
Loyau, S.; Dumont, B.; Ollivier, V.; Boulaftali, Y.; Feldman, L.; Ajzenberg, N.; Jandrot-Perrus, M. Platelet glycoprotein VI dimerization, an active process inducing receptor competence, is an indicator of platelet reactivity. Arterioscler. Thromb. Vasc. Biol., 2012, 32(3), 778-785.[] [PMID: 22155453]
Stroop, S.D.; Beavo, J.A. Structure and function studies of the cGMP-stimulated phosphodiesterase. J. Biol. Chem., 1991, 266(35), 23802-23809.[] [PMID: 1721055]
Turko, I.V.; Francis, S.H.; Corbin, J.D. Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. Biochem. J., 1998, 329(Pt 3), 505-510.[] [PMID: 9445376]
Yang, J.; Wu, J.; Kowalska, M.A.; Dalvi, A.; Prevost, N.; O’Brien, P.J.; Manning, D.; Poncz, M.; Lucki, I.; Blendy, J.A.; Brass, L.F. Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs. Proc. Natl. Acad. Sci. USA, 2000, 97(18), 9984-9989.[] [PMID: 10954748]
Hechler, B.; Gachet, C. Purinergic receptors in thrombosis and inflammation. Arterioscler. Thromb. Vasc. Biol., 2015, 35(11), 2307-2315.[] [PMID: 26359511]
Margarucci, L.; Roest, M.; Preisinger, C.; Bleijerveld, O.B.; van Holten, T.C.; Heck, A.J.R.; Scholten, A. Collagen stimulation of platelets induces a rapid spatial response of cAMP and cGMP signaling scaffolds. Mol. Biosyst., 2011, 7(7), 2311-2319.[] [PMID: 21597619]
Bodin, S.; Tronchère, H.; Payrastre, B. Lipid rafts are critical membrane domains in blood platelet activation processes. Biochim. Biophys. Acta, 2003, 1610(2), 247-257.[] [PMID: 12648778]
Quinton, T.M.; Kim, S.; Jin, J.; Kunapuli, S.P. Lipid rafts are required in Galpha(i) signaling downstream of the P2Y12 receptor during ADP-mediated platelet activation. J. Thromb. Haemost., 2005, 3(5), 1036-1041.[] [PMID: 15869601]
Leggas, M.; Adachi, M.; Scheffer, G.L.; Sun, D.; Wielinga, P.; Du, G.; Mercer, K.E.; Zhuang, Y.; Panetta, J.C.; Johnston, B.; Scheper, R.J.; Stewart, C.F.; Schuetz, J.D. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell. Biol., 2004, 24(17), 7612-7621.[] [PMID: 15314169]
Sassi, Y.; Abi-Gerges, A.; Fauconnier, J.; Mougenot, N.; Reiken, S.; Haghighi, K.; Kranias, E.G.; Marks, A.R.; Lacampagne, A.; Engelhardt, S.; Hatem, S.N.; Lompre, A.M.; Hulot, J.S. Regulation of cAMP homeostasis by the efflux protein MRP4 in cardiac myocytes. FASEB J., 2012, 26(3), 1009-1017.[] [PMID: 22090316]
Decouture, B.; Dreano, E.; Belleville-Rolland, T.; Kuci, O.; Dizier, B.; Bazaa, A.; Coqueran, B.; Lompre, A.M.; Denis, C.V.; Hulot, J.S.; Bachelot-Loza, C.; Gaussem, P. Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice. Blood, 2015, 126(15), 1823-1830.[] [PMID: 26316625]
Hiasa, M.; Togawa, N.; Miyaji, T.; Omote, H.; Yamamoto, A.; Moriyama, Y. Essential role of vesicular nucleotide transporter in vesicular storage and release of nucleotides in platelets. Physiol. Rep., 2014, 2(6), e12034.[] [PMID: 24907298]
Shrimpton, C.N.; Borthakur, G.; Larrucea, S.; Cruz, M.A.; Dong, J.F.; López, J.A. Localization of the adhesion receptor glycoprotein Ib-IX-V complex to lipid rafts is required for platelet adhesion and activation. J. Exp. Med., 2002, 196(8), 1057-1066.[] [PMID: 12391017]
Belleville-Rolland, T.; Sassi, Y.; Decouture, B.; Dreano, E.; Hulot, J.S.; Gaussem, P.; Bachelot-Loza, C. MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. Pharmacol. Res., 2016, 107, 381-389.[] [PMID: 27063943]
Raslan, Z.; Naseem, K.M. Compartmentalisation of cAMP-dependent signalling in blood platelets: the role of lipid rafts and actin polymerisation. Platelets, 2015, 26(4), 349-357.[] [PMID: 24832788]
Raslan, Z.; Aburima, A.; Naseem, K.M. The spatiotemporal regulation of cAMP Signaling in blood platelets-old friends and new players. Front. Pharmacol., 2015, 6(Nov), 266.[] [PMID: 26617518]
Borgognone, A.; Pulcinelli, F.M. Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport. Thromb. Haemost., 2012, 108(5), 955-962.[] [PMID: 23014861]
Lien, L-M.; Chen, Z-C.; Chung, C-L.; Yen, T-L.; Chiu, H-C.; Chou, D-S.; Huang, S-Y.; Sheu, J-R.; Lu, W-J.; Lin, K-H. Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo. Eur. J. Pharmacol., 2014, 737, 159-167.[] [PMID: 24836986]
Niessen, J.; Jedlitschky, G.; Grube, M.; Kawakami, H.; Kamiie, J.; Ohtsuki, S.; Schwertz, H.; Bien, S.; Starke, K.; Ritter, C.; Strobel, U.; Greinacher, A.; Terasaki, T.; Kroemer, H.K. Expression of ABC-type transport proteins in human platelets. Pharmacogenet. Genomics, 2010, 20(6), 396-400.[] [PMID: 20395880]
Sjölinder, M.; Tornhamre, S.; Claesson, H.E.; Hydman, J.; Lindgren, J. Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1. J. Lipid Res., 1999, 40(3), 439-446.[] [PMID: 10064732]
Sassi, Y.; Lipskaia, L.; Vandecasteele, G.; Nikolaev, V.O.; Hatem, S.N.; Cohen Aubart, F.; Russel, F.G.; Mougenot, N.; Vrignaud, C.; Lechat, P.; Lompré, A-M.; Hulot, J-S. 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.[] [PMID: 18636120]
Vogt, K.; Mahajan-Thakur, S.; Wolf, R.; Bröderdorf, S.; Vogel, C.; Böhm, A.; Ritter, C.A.; Gräler, M.; Oswald, S.; Greinacher, A.; Kroemer, H.K.; Jedlitschky, G.; Rauch, B.H. 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.[] [PMID: 29304533]
Decouture, B.; Becker, P.H.; Therond, P.; Gaussem, P.; Bachelot-Loza, C. Evidence that MRP4 is only partly involved in S1P secretion during platelet activation. Thromb. Haemost., 2018, 118(6), 1116-1118.[] [PMID: 29669387]
Mendes-Silverio, C.B.; Lescano, C.H.; Zaminelli, T.; Sollon, C.; Anhê, G.F.; Antunes, E.; Mónica, F.Z. Activation of soluble guanylyl cyclase with inhibition of multidrug resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy. Biochem. Pharmacol., 2018, 152(January), 165-173.[] [PMID: 29605625]
Berger, J.S.; Brown, D.L.; Becker, R.C. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am. J. Med., 2008, 121(1), 43-49.[] [PMID: 18187072]
Gasparyan, A.Y.; Watson, T.; Lip, G.Y.H. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J. Am. Coll. Cardiol., 2008, 51(19), 1829-1843.[] [PMID: 18466797]
Lee, P.Y.; Chen, W.H.; Ng, W.; Cheng, X.; Kwok, J.Y.Y.; Tse, H.F.; Lau, C.P. Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. Am. J. Med., 2005, 118(7), 723-727.[] [PMID: 15989905]
Mason, P.J.; Jacobs, A.K.; Freedman, J.E. Aspirin resistance and atherothrombotic disease. J. Am. Coll. Cardiol., 2005, 46(6), 986-993.[] [PMID: 16168280]
Chen, C.; Klaassen, C.D. Rat multidrug resistance protein 4 (Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal expression, and chemical inducibility. Biochem. Biophys. Res. Commun., 2004, 317(1), 46-53.[] [PMID: 15047146]
Massimi, I.; Guerriero, R.; Lotti, L.V.; Lulli, V.; Borgognone, A.; Romani, F.; Barillà, F.; Gaudio, C.; Gabbianelli, M.; Frati, L.; Pulcinelli, F.M. Aspirin influences megakaryocytic gene expression leading to up-regulation of multidrug resistance protein-4 in human platelets. Br. J. Clin. Pharmacol., 2014, 78(6), 1343-1353.[] [PMID: 24902864]
Massimi, I.; Ciuffetta, A.; Temperilli, F.; Ferrandino, F.; Zicari, A.; Pulcinelli, F.M.; Felli, M.P. Multidrug resistance protein-4 influences aspirin toxicity in human cell line. Mediators Inflamm., 2015, 2015(13), 607957.[] [PMID: 26491233]
Temperilli, F.; Di Franco, M.; Massimi, I.; Guarino, M.L.; Guzzo, M.P.; Valesini, G.; Frati, L.; Pulcinelli, F.M. 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.[] [PMID: 26141932]
Massimi, I.; Alemanno, L.; Maria, S.; Scd, L. G.; Guerriero, R.; Frati, L.; Biasucci, L.; Pulcinelli, F. M. MiR-21 role in aspirin- dependent PPARα and multidrug resistance protein 4 upregulation. 2018, 2017, 596-606.
La Rosa, G.; Biasucci, L.M.; Mandolini, C.; Massimi, I.; Copponi, G.; Pulcinelli, F.M.; Crea, F. Platelet miRNA-26b down-regulates multidrug resistance protein 4 in patients on chronic aspirin treatment. J. Cardiovasc. Med. (Hagerstown), 2018, 19(10), 611-613.[] [PMID: 30015780]
Alemanno, L.; Massimi, I.; Klaus, V.; Guarino, M.L.; Maltese, T.; Frati, L.; Angiolillo, D.J.; Pulcinelli, F.M. 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.[] [PMID: 29448294]
Giona, F.; Massimi, I.; Guarino, M.L.; Santopietro, M.; Laurino, M.; Temperilli, F.; Palumbo, G.; Foà, R.; Pulcinelli, F.M. Platelet activation and multidrug resistance protein-4 expression in children and adolescents with different subtypes of primary thrombocythemia. Haematologica, 2020, 105(2), e65-e67.[] [PMID: 31171639]
Guarino, M.L.; Massimi, I.; Alemanno, L.; Conti, L.; Angiolillo, D.J.; Pulcinelli, F.M. MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation. J. Thromb. Thrombolysis, 2021, 51(3), 625-632.[] [PMID: 32803738]
Cheung, L.; Flemming, C.L.; Watt, F.; Masada, N.; Yu, D.M.T.; Huynh, T.; Conseil, G.; Tivnan, A.; Polinsky, A.; Gudkov, A.V.; Munoz, M.A.; Vishvanath, A.; Cooper, D.M.F.; Henderson, M.J.; Cole, S.P.C.; Fletcher, J.I.; Haber, M.; Norris, M.D. 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.[] [PMID: 24973542]
Wolf, R.; Grammbauer, S.; Boehm, A.; Jedlitschky, G.; Rauch, B. H. P6067Specific inhibition of MRP4/ABCC4 decreases calcium influx and glycoprotein IIb/IIIa activation in human platelets. Eur. Heart J., 2018, 39(1), 4.[]
Li, J.; Chen, Y.; Ou, Z.; Ouyang, F.; Liang, J.; Jiang, Z.; Chen, C.; Li, P.; Chen, J.; Wei, J.; Zeng, J. Aspirin therapy in cardiovascular disease with glucose-6-phosphate dehydrogenase deficiency, safe or not? Am. J. Cardiovasc. Drugs, 2021, 21(4), 377-382.[] [PMID: 33313989]

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Year: 2021
Published on: 19 May, 2021
Page: [983 - 995]
Pages: 13
DOI: 10.2174/0929866528666210505120659
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