Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 1/2023

28-07-2021 | Ticagrelor | Review Article

The Function and Regulation of Platelet P2Y12 Receptor

Authors: Xiaohua Li, Guoxing Zhang, Xia Cao

Published in: Cardiovascular Drugs and Therapy | Issue 1/2023

Login to get access

Abstract

In addition to the key role in hemostasis and thrombosis, platelets have also been wildly acknowledged as immune regulatory cells and involving in the pathogenesis of inflammation-related diseases. Since purine receptor P2Y12 plays a crucial role in platelet activation, P2Y12 antagonists such as clopidogrel, prasugrel, and ticagrelor have been widely used in cardiovascular diseases worldwide in recent decades due to their potent antiplatelet and antithrombotic effects. Meanwhile, the role of P2Y12 in inflammatory diseases has also been extensively studied. Relatively, there are few studies on the regulation of P2Y12. This review first summarizes the various roles of P2Y12 in the process of platelet activation, as well as downstream effects and signaling pathways; then introduces the effects of P2Y12 in inflammatory diseases such as sepsis, atherosclerosis, cancer, autoimmune diseases, and asthma; and finally reviews the current researches on P2Y12 regulation.
Literature
1.
Wong C, et al. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013;14(8):785–92.CrossRef
2.
Yeung J, Li W, Holinstat M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev. 2018;70(3):526–48.CrossRef
3.
Mezger M, et al. Platelets and immune responses during thromboinflammation. Front Immunol. 2019;10:1731.CrossRef
4.
Eriksson O, et al. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol. 2019;10:1590.CrossRef
5.
Cattaneo M. P2Y12 receptors: structure and function. J Thromb Haemost. 2015;13:S10–6.CrossRef
6.
Hollopeter G, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409(6817):202–7.CrossRef
7.
Zhang FL, et al. ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem. 2001;276(11):8608–15.CrossRef
8.
Ohlmann P, et al. The platelet P2Y(12) receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [(3)H]PSB-0413. Purinergic Signal. 2013;9(1):59–66.CrossRef
9.
Haynes SE, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006;9(12):1512–9.CrossRef
10.
Wihlborg AK, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol. 2004;24(10):1810–5.CrossRef
11.
Hogberg C, et al. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol. 2010;142(2):187–92.CrossRef
12.
Ben Addi A, et al. Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. J Immunol. 2010;185(10):5900–6.CrossRef
13.
Kronlage M, et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci Signal. 2010;3(132):ra55.CrossRef
14.
Neves JS, Radke AL, Weller PF. Cysteinyl leukotrienes acting via granule membrane-expressed receptors elicit secretion from within cell-free human eosinophil granules. J Allergy Clin Immunol. 2010;125(2):477–82.CrossRef
15.
Muniz VS, et al. Purinergic P2Y12 receptor activation in eosinophils and the schistosomal host response. PLoS One. 2015;10(10):e0139805.CrossRef
16.
Su X, et al. The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. J Clin Invest. 2012;122(10):3579–92.CrossRef
17.
Mediero A, et al. Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. FASEB J. 2016;30(11):3887–900.CrossRef
18.
Elaskalani O, et al. Antiplatelet drug ticagrelor enhances chemotherapeutic efficacy by targeting the novel P2Y12-AKT pathway in pancreatic cancer cells. Cancers. 2020;12(1):250.CrossRef
19.
Sarangi S, et al. P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer. Med Oncol. 2013;30(2):567.CrossRef
20.
Krzemiński P, et al. Expression and functional characterization of P2Y1 and P2Y12 nucleotide receptors in long-term serum-deprived glioma C6 cells. FEBS J. 2007;274(8):1970–82.CrossRef
21.
Jin J, et al. The C6–2B glioma cell P2Y(AC) receptor is pharmacologically and molecularly identical to the platelet P2Y(12) receptor. Br J Pharmacol. 2001;133(4):521–8.CrossRef
22.
Hechler B, et al. The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol. 1998;103(3):858–66.CrossRef
23.
Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem. 1998;273(4):2030–4.CrossRef
24.
Turner NA, Moake JL, McIntire LV. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood. 2001;98(12):3340–5.CrossRef
25.
Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal. 2012;8(3):609–19.CrossRef
26.
Cattaneo M, et al. Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood. 1990;75(5):1081–6.CrossRef
27.
Storey RF, et al. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol. 2000;110(4):925–34.CrossRef
28.
Shankar H, et al. P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost. 2006;4(3):638–47.CrossRef
29.
Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23(4):177–89.CrossRef
30.
Ponomarev ED. Fresh evidence for platelets as neuronal and innate immune cells: their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation. Front Immunol. 2018;9:406.CrossRef
31.
Thomas MR, Storey RF. Effect of P2Y12 inhibitors on inflammation and immunity. Thromb Haemost. 2015;114(3):490–7.
32.
Anderson R, et al. ADP-mediated upregulation of expression of CD62P on human platelets is critically dependent on co-activation of P2Y1 and P2Y12 receptors. Pharmaceuticals. 2020;13(12):420.CrossRef
33.
Suzuki J, et al. Cytokine secretion from human monocytes potentiated by P-selectin-mediated cell adhesion. Int Arch Allergy Immunol. 2013;160(2):152–60.CrossRef
34.
Neumann F, et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation. 1997;95(10):2387–94.CrossRef
35.
Carestia A, et al. Platelets promote macrophage polarization toward pro-inflammatory phenotype and increase survival of septic mice. Cell Rep. 2019;28(4):896-908.e5.CrossRef
36.
Badrnya S, et al. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol. 2014;34(3):571–80.CrossRef
37.
Etulain J, et al. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126(2):242–6.CrossRef
38.
Barnard M, et al. Effects of platelet binding on whole blood flow cytometry assays of monocyte and neutrophil procoagulant activity. J Thromb Haemost. 2005;3(11):2563–70.CrossRef
39.
Evangelista V, et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost. 2005;94(3):568–77.
40.
Totani L, et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012;107(06):1130–40.CrossRef
41.
Leon C, et al. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol. 2003;23(10):1941–7.CrossRef
42.
Dorsam RT, Tuluc M, Kunapuli SP. Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb Haemost. 2004;2(5):804–12.CrossRef
43.
van der Meijden PE, et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost. 2005;93(6):1128–36.CrossRef
44.
Leon C, et al. Platelet ADP receptors contribute to the initiation of intravascular coagulation. Blood. 2004;103(2):594–600.CrossRef
45.
Gąsecka A, et al. Role of P2Y receptors in platelet extracellular vesicle release. Int J Mol Sci. 2020;21(17):6065.CrossRef
46.
Rosinska J, Lukasik M, Kozubski W. The impact of vascular disease treatment on platelet-derived microvesicles. Cardiovasc Drugs Ther. 2017;31(5–6):627–44.CrossRef
47.
Giacomazzi A, et al. Antiplatelet agents inhibit the generation of platelet-derived microparticles. Front Pharmacol. 2016;7:314.CrossRef
48.
Gasecka A, et al. P2Y12 antagonist ticagrelor inhibits the release of procoagulant extracellular vesicles from activated platelets. Cardiol J. 2019;26(6):782–9.CrossRef
49.
Zhang Y, et al. Contact- and agonist-regulated microvesiculation of human platelets. Thromb Haemost. 2013;110(2):331–9.
50.
França CN, et al. Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease. Circ J. 2012;76(3):729–36.CrossRef
51.
Kafian S, et al. Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome. Platelets. 2015;26(5):467–73.CrossRef
52.
Kalantzi KI, et al. The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment. Platelets. 2012;23(2):121–31.CrossRef
53.
Gasecka A, et al. Ticagrelor attenuates the increase of extracellular vesicle concentrations in plasma after acute myocardial infarction compared to clopidogrel. J Thromb Haemost. 2020;18(3):609–23.CrossRef
54.
Hafiane A, Daskalopoulou SS. Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease. Metabolism. 2018;85:213–22.CrossRef
55.
Chyrchel B, et al. Platelet reactivity and circulating platelet-derived microvesicles are differently affected by P2Y12 receptor antagonists. Int J Med Sci. 2019;16(2):264–75.CrossRef
56.
Zhang S, et al. P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation. J Thromb Haemost. 2013;11(1):149–60.CrossRef
57.
Meng X, et al. Ticagrelor prevents tumor metastasis via inhibiting cell proliferation and promoting platelet apoptosis. Anticancer Drugs. 2020;31(10):1012–7.CrossRef
58.
Ouseph MM, et al. Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. Blood. 2015;126(10):1224–33.CrossRef
59.
Malaver E, et al. NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost. 2009;7(8):1333–43.CrossRef
60.
Cattaneo M, et al. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood. 1992;80(11):2787–96.CrossRef
61.
Nurden P, et al. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function. J Clin Invest. 1995;95(4):1612–22.CrossRef
62.
Cattaneo M, et al. Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet ‘primary secretion defect’ are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol. 2000;20(11):E101–6.CrossRef
63.
Cattaneo M, et al. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci U S A. 2003;100(4):1978–83.CrossRef
64.
Shiraga M, et al. Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost. 2005;3(10):2315–23.CrossRef
65.
Daly ME, et al. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study. Blood. 2009;113(17):4110–3.CrossRef
66.
Nisar S, et al. An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets. Blood. 2011;118(20):5641–51.CrossRef
67.
Patel YM, et al. A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J Thromb Haemost. 2014;12(5):716–25.CrossRef
68.
Lecchi A, et al. Inherited dysfunctional platelet P2Y(12) receptor mutations associated with bleeding disorders. Hamostaseologie. 2016;36(4):279–83.CrossRef
69.
Mundell SJ, et al. Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding. J Thromb Haemost. 2018;16(1):44–53.CrossRef
70.
Zhang K, et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014;509(7498):115–8.CrossRef
71.
Gao Y, et al. The role of P2Y12 receptor in ischemic stroke of atherosclerotic origin. Cell Mol Life Sci. 2018;76(2):341–54.CrossRef
72.
Ito Y, et al. Vasodilator-stimulated phosphoprotein (VASP) is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and antiplatelet effect of prasugrel in rats. Sci Rep. 2018;8(1):9955.CrossRef
73.
Massberg S, et al. Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)-deficient mice. Blood. 2004;103(1):136–42.CrossRef
74.
Aszódi A, et al. The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function. Embo j. 1999;18(1):37–48.CrossRef
75.
Schwarz UR, et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets–definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999;82(3):1145–52.CrossRef
76.
Trumel C, et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood. 1999;94(12):4156–65.CrossRef
77.
Woulfe D, et al. Activation of Rap1B by G(i) family members in platelets. J Biol Chem. 2002;277(26):23382–90.CrossRef
78.
Cattaneo M. The platelet P2Y(1)(2) receptor for adenosine diphosphate: congenital and drug-induced defects. Blood. 2011;117(7):2102–12.CrossRef
79.
Garcia A, et al. Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways. Biochem J. 2010;429(2):369–77.CrossRef
80.
Miao J, Liu R, Li Z. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(21):2250–1.
81.
Sugidachi A, et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129(7):1439–46.CrossRef
82.
Kamran H, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021;325(15):1545–55.CrossRef
83.
You S, et al. Association of Ticagrelor vs Clopidogrel With Net Adverse Clinical Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. JAMA. 2020;324(16):1640–50.CrossRef
84.
Armstrong D, et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19(2):209–19.CrossRef
85.
Franchi F, et al. Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Circulation. 2019;139(14):1661–70.CrossRef
86.
Wolf D, Ley K. Immunity and Inflammation in Atherosclerosis. Circ Res. 2019;124(2):315–27.CrossRef
87.
Penz SM, et al. Glycoprotein Ibalpha inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques. Thromb Haemost. 2007;97(3):435–43.CrossRef
88.
Nergiz-Unal R, et al. Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques. PLoS One. 2010;5(4):e10130.CrossRef
89.
Afek A, et al. Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res. 2009;77(3):364–9.CrossRef
90.
Heim C, et al. Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo. Heart Vessels. 2016;31(5):783–94.CrossRef
91.
Ganbaatar B, et al. Ticagrelor, a P2Y12 antagonist, attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein-E-deficient mice. Atherosclerosis. 2018;275:124–32.CrossRef
92.
Li D, et al. Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32(8):e81–9.CrossRef
93.
West LE, et al. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res. 2014;102(3):429–35.CrossRef
94.
Pi S, et al. The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy. 2021;17(4):980–1000.CrossRef
95.
Chen X, et al. Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice. Arterioscler Thromb Vasc Biol. 2017;37(1):75–83.CrossRef
96.
Mendolicchio GL, et al. Variable effect of P2Y12 inhibition on platelet thrombus volume in flowing blood. J Thromb Haemost. 2011;9(2):373–82.CrossRef
97.
Chen Y, et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J. 2006;119(1):32–6.CrossRef
98.
Lowenstern A, et al. Platelet-related biomarkers and their response to inhibition with aspirin and p2y(12)-receptor antagonists in patients with acute coronary syndrome. J Thromb Thrombolysis. 2017;44(2):145–53.CrossRef
99.
Sakata T, Kario K. Antiplatelet therapy effectively reduces plasma plasminogen activator inhibitor-1 levels. Atherosclerosis. 2011;214(2):490–1.CrossRef
100.
Yi X, et al. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. J Stroke Cerebrovasc Dis. 2014;23(7):1975–81.CrossRef
101.
An X, et al. Inhibition of platelets by clopidogrel suppressed Ang II-induced vascular inflammation, oxidative stress, and remodeling. J Am Heart Assoc. 2018;7(21):e009600.CrossRef
102.
Liu O, et al. Clopidogrel, a platelet P2Y12 receptor inhibitor, reduces vascular inflammation and angiotensin II induced-abdominal aortic aneurysm progression. PLoS One. 2012;7(12):e51707.CrossRef
103.
Wang Y, et al. Platelet activation and antiplatelet therapy in sepsis: A narrative review. Thromb Res. 2018;166:28–36.CrossRef
104.
Assinger A, et al. Platelets in sepsis: an update on experimental models and clinical data. Front Immunol. 2019;10:1687.CrossRef
105.
Soriano AO, et al. Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis. Crit Care Med. 2005;33(11):2540–6.CrossRef
106.
Naime ACA, Ganaes JOF, Lopes-Pires ME. Sepsis: the involvement of platelets and the current treatments. Curr Mol Pharmacol. 2018;11(4):261–9.CrossRef
107.
Hamzeh-Cognasse H, et al. Platelets and infections - complex interactions with bacteria. Front Immunol. 2015;6:82.CrossRef
108.
Hannachi N, et al. Antiplatelet agents have a distinct efficacy on platelet aggregation induced by infectious bacteria. Front Pharmacol. 2020;11:863.CrossRef
109.
Wang XL, et al. Clopidogrel reduces lipopolysaccharide-induced inflammation and neutrophil-platelet aggregates in an experimental endotoxemic model. J Biochem Mol Toxicol. 2019;33(4):e22279.CrossRef
110.
Rahman M, et al. Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis. Platelets. 2014;25(4):257–63.CrossRef
111.
Liverani E, et al. P2Y12 receptor modulates sepsis-induced inflammation. Arterioscler Thromb Vasc Biol. 2016;36(5):961–71.CrossRef
112.
Li X, et al. The protective effect of ticagrelor on renal function in a mouse model of sepsis-induced acute kidney injury. Platelets. 2018;30(2):199–205.CrossRef
113.
Seidel M, et al. Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost. 2009;7(6):1030–2.CrossRef
114.
Liverani E, et al. LPS-induced systemic inflammation is more severe in P2Y12 null mice. J Leukoc Biol. 2014;95(2):313–23.CrossRef
115.
Claushuis TAM, et al. Platelet-dense granules worsen pre-infection thrombocytopenia during gram-negative pneumonia-derived sepsis. J Innate Immun. 2019;11(2):168–80.CrossRef
116.
Albayati S, et al. P2Y(12) antagonism results in altered interactions between platelets and regulatory T cells during sepsis. J Leukoc Biol. 2020;110(1):141–53.CrossRef
117.
Thomas MR, et al. Platelet P2Y12 inhibitors reduce systemic inflammation and its prothrombotic effects in an experimental human model. Arterioscler Thromb Vasc Biol. 2015;35(12):2562–70.CrossRef
118.
Schoergenhofer C, et al. Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial. Clin Sci. 2016;130(6):433–40.CrossRef
119.
Kiers D, et al. A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia. Thromb Haemost. 2017;117(9):1798–807.CrossRef
120.
Dewitte A, et al. Correction to: Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critically ill patients? Ann Intensive Care. 2018;8(1):32.CrossRef
121.
Sexton TR, et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci. 2018;3(4):435–49.CrossRef
122.
Tsai MJ, et al. Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study. Intensive Care Med. 2015;41(5):806–13.CrossRef
123.
Kim T, et al. Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke. Eur J Neurol. 2019;26(2):261–7.CrossRef
124.
125.
Storey R, et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets. 2014;25(7):517–25.CrossRef
126.
Long H, et al. Risk of infections in patients treated with ticagrelor versus clopidogrel: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2021;7(3):171–9.
127.
Huang B, et al. Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y(12) signaling pathway. Cell Mol Immunol. 2020;18(5):1278–89.CrossRef
128.
Lancellotti P, et al. Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant gram-positive bacteria. JAMA Cardiol. 2019;4(6):596–9.CrossRef
129.
Elaskalani O, et al. Targeting platelets for the treatment of cancer. Cancers (Basel). 2017;9(7):94.CrossRef
130.
Gresele P, Malvestiti M, Momi S. Anti-platelet treatments in cancer: Basic and clinical research. Thromb Res. 2018;164:S106–11.CrossRef
131.
Cho MS, et al. Role of ADP receptors on platelets in the growth of ovarian cancer. Blood. 2017;130(10):1235–42.CrossRef
132.
Bambace NM, Levis JE, Holmes CE. The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets. Platelets. 2010;21(2):85–93.CrossRef
133.
Battinelli EM, Markens BA, Italiano JE Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood. 2011;118(5):1359–69.CrossRef
134.
Wu H, et al. The angiogenic responses induced by release of angiogenic proteins from tumor cell-activated platelets are regulated by distinct molecular pathways. IUBMB Life. 2015;67(8):626–33.CrossRef
135.
Holmes CE, et al. Platelet phenotype changes associated with breast cancer and its treatment. Platelets. 2016;27(7):703–11.CrossRef
136.
Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576–90.CrossRef
137.
Kubota SI, et al. Whole-organ analysis of TGF-β-mediated remodelling of the tumour microenvironment by tissue clearing. Commun Biol. 2021;4(1):294.CrossRef
138.
Chen H, et al. Direct TGF-β1 signaling between activated platelets and pancreatic cancer cells primes cisplatin insensitivity. Cell Biol Int. 2013;37(5):478–84.CrossRef
139.
Kalinichenko, Vladimir V, et al. Platelet P2Y12 is involved in murine pulmonary metastasis. PLoS ONE. 2013;8(11):e80780.CrossRef
140.
Wang D, et al. Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology. 2015;149(7):1884-1895.e4.CrossRef
141.
Nandi P, et al. PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer. 2017;17(1):11.CrossRef
142.
Guillem-Llobat P, et al. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget. 2016;7(22):32462–77.CrossRef
143.
Gebremeskel S, et al. The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int J Cancer. 2015;136(1):234–40.CrossRef
144.
Gareau AJ, et al. Ticagrelor inhibits platelet-tumor cell interactions and metastasis in human and murine breast cancer. Clin Exp Metastasis. 2018;35(1–2):25–35.CrossRef
145.
Rodríguez-Miguel A, et al. Clopidogrel and low-dose aspirin, alone or together, reduce risk of colorectal cancer. Clin Gastroenterol Hepatol. 2019;17(10):2024-2033.e2.CrossRef
146.
Leader A, et al. The effect of combined aspirin and clopidogrel treatment on cancer incidence. Am J Med. 2017;130(7):826–32.CrossRef
147.
Kuan YC, et al. Effects of aspirin or clopidogrel on colorectal cancer chemoprevention in patients with type 2 diabetes mellitus. Cancers (Basel). 2019;11(10):1468.CrossRef
148.
Hayashi T, et al. Antiplatelet therapy improves the prognosis of patients with hepatocellular carcinoma. Cancers (Basel). 2020;12(11):3215.CrossRef
149.
Cairat M, et al. Antiplatelet drug use and breast cancer risk in a prospective cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2021;30(4):643–52.CrossRef
150.
Elmariah S, et al. Impact of clopidogrel therapy on mortality and cancer in patients with cardiovascular and cerebrovascular disease: a patient-level meta-analysis. Circulation Cardiovascular interventions. 2018;11(1):e005795.CrossRef
151.
Hicks B, et al. Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients. Pharmacoepidemiol Drug Saf. 2015;24(8):830–40.CrossRef
152.
Raposeiras-Roubín S, et al. Risk of cancer after an acute coronary syndrome according to the type of P2Y12 inhibitor. Thromb Res. 2019;174:51–8.CrossRef
153.
Duffau P, et al. Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med. 2010;2(47):47ra63.CrossRef
154.
Wang L, et al. Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus. J Thromb Haemost. 2004;2(8):1436–42.CrossRef
155.
Harifi G, Sibilia J. Pathogenic role of platelets in rheumatoid arthritis and systemic autoimmune diseases. Perspectives and therapeutic aspects. Saudi Med J. 2016;37(4):354–60.CrossRef
156.
Lukasik ZM, Makowski M, Makowska JS. From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol Int. 2018;38(6):959–74.CrossRef
157.
Frey O, et al. Erosive arthritis and hepatic granuloma formation induced by peptidoglycan polysaccharide in rats is aggravated by prasugrel treatment. PLoS ONE. 2013;8(7):e69093.CrossRef
158.
Garcia AE, et al. Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One. 2011;6(10):e26035.CrossRef
159.
Takeda T, et al. Recent advances in understanding the roles of blood platelets in the pathogenesis of allergic inflammation and bronchial asthma. Allergol Int. 2018;67(3):326–33.CrossRef
160.
Mansour A, et al. P2Y12 inhibition beyond thrombosis: effects on inflammation. International Journal of Molecular Sciences. 2020;21(4):1391.CrossRef
161.
Paruchuri S, et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med. 2009;206(11):2543–55.CrossRef
162.
Suh DH, et al. P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma. J Cell Mol Med. 2016;20(2):333–41.CrossRef
163.
Laidlaw TM, et al. A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2019;143(1):316-324.e7.CrossRef
164.
Lussana F, et al. Effect of prasugrel in patients with asthma: results of PRINA, a randomized, double-blind, placebo-controlled, cross-over study. J Thromb Haemost. 2015;13(1):136–41.CrossRef
165.
Mundell SJ, et al. Rapid resensitization of purinergic receptor function in human platelets. J Thromb Haemost. 2008;6(8):1393–404.CrossRef
166.
Hardy AR, et al. P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood. 2005;105(9):3552–60.CrossRef
167.
Chaudhary P, et al. Role of GRK6 in the regulation of platelet activation through selective G protein-coupled receptor (GPCR) desensitization. Int J Mol Sci. 2020;21(11):3932.CrossRef
168.
Nagy B Jr, et al. Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. J Thromb Haemost. 2011;9(4):810–9.CrossRef
169.
Haberstock-Debic H, et al. A clopidogrel-insensitive inducible pool of P2Y12 receptors contributes to thrombus formation: inhibition by elinogrel, a direct-acting, reversible P2Y12 antagonist. J Pharmacol Exp Ther. 2011;339(1):54–61.CrossRef
170.
Koessler J, et al. The role of agonist-induced activation and inhibition for the regulation of purinergic receptor expression in human platelets. Thromb Res. 2018;168:40–6.CrossRef
171.
Periayah MH, et al. Glycoprotein IIb/IIIa and P2Y12 induction by oligochitosan accelerates platelet aggregation. Biomed Res Int. 2014;2014:653149.CrossRef
172.
Shanker G, et al. Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J Thromb Thrombolysis. 2006;22(3):213–20.CrossRef
173.
Hu L, et al. Platelets express activated P2Y12 receptor in patients with diabetes mellitus. Circulation. 2017;136(9):817–33.CrossRef
174.
Fejes Z, et al. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost. 2017;117(3):529–42.CrossRef
175.
Nagalla S, et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood. 2011;117(19):5189–97.CrossRef
176.
Szilagyi B, et al. Role of sepsis modulated circulating microRNAs. EJIFCC. 2019;30(2):128–45.
177.
Shi R, et al. The emerging role of miR-223 in platelet reactivity: implications in antiplatelet therapy. Biomed Res Int. 2015;2015:981841.CrossRef
178.
Shi R, et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res. 2013;131(6):508–13.CrossRef
179.
Zhang YY, 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. 2014;38(1):65–72.CrossRef
180.
Landry P, et al. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009;16(9):961–6.CrossRef
181.
Kaudewitz D, et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res. 2016;118(3):420–32.CrossRef
182.
Zhou M, et al. Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model. Platelets. 2019;30(4):452–9.CrossRef
183.
Rauch BH, et al. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol. 2010;30(12):2434–42.CrossRef
184.
Li J-J, et al. Antiplatelet drug ticagrelor delays gastric ulcer healing in rats. Exp Ther Med. 2017;14(4):3774–9.CrossRef
185.
Pels K, et al. Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs. Eur J Clin Invest. 2009;39(3):174–82.CrossRef
Metadata
Title
The Function and Regulation of Platelet P2Y12 Receptor
Authors
Xiaohua Li
Guoxing Zhang
Xia Cao
Publication date
28-07-2021
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 1/2023
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07229-4

Other articles of this Issue 1/2023

Cardiovascular Drugs and Therapy 1/2023 Go to the issue

Original Article

Single-Dose Intraprocedural Steroid Administration Does Not Impact Early Atrial Fibrillation Recurrence

Invited Editorial

Bioresorbable Vascular Scaffolds: a Dissolving Dream?

Original Article

Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3

Original Article

Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

Review Article

The Function and Therapeutic Potential of Circular RNA in Cardiovascular Diseases

Correction

Correction to: The Comparative Effectiveness and Safety of Different Anticoagulation Strategies for Treatment of Left Atrial Appendage Thrombus in the Setting of Chronic Anticoagulation for Atrial Fibrillation or Flutter