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Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions.
Rigg RA, Healy LD, Chu TT, Ngo ATP, Mitrugno A, Zilberman-Rudenko J, Aslan JE, Hinds MT, Vecchiarelli LD, Morgan TK, Gruber A, Temple KJ, Lindsley CW, Duvernay MT, Hamm HE, McCarty OJT
(2019) Platelets 30: 126-135
MeSH Terms: Animals, Biomarkers, Blood Platelets, Cell Communication, Cytoplasmic Granules, Flow Cytometry, Humans, Leukocytes, Male, Papio, Platelet Activation, Platelet Aggregation, Receptors, Thrombin
Show Abstract · Added March 24, 2020
Human platelets express two protease-activated receptors (PARs), PAR1 (F2R) and PAR4 (F2RL3), which are activated by a number of serine proteases that are generated during pathological events and cause platelet activation. Recent interest has focused on PAR4 as a therapeutic target, given PAR4 seems to promote experimental thrombosis and procoagulant microparticle formation, without a broadly apparent role in hemostasis. However, it is not yet known whether PAR4 activity plays a role in platelet-leukocyte interactions, which are thought to contribute to both thrombosis and acute or chronic thrombo-inflammatory processes. We sought to determine whether PAR4 activity contributes to granule secretion from activated platelets and platelet-leukocyte interactions. We performed in vitro and ex vivo studies of platelet granule release and platelet-leukocyte interactions in the presence of PAR4 agonists including PAR4 activating peptide, thrombin, cathepsin G, and plasmin in combination with small-molecule PAR4 antagonists. Activation of human platelets with thrombin, cathepsin G, or plasmin potentiated platelet dense granule secretion that was specifically impaired by PAR4 inhibitors. Platelet-leukocyte interactions and platelet P-selectin exposure the following stimulation with PAR4 agonists were also impaired by activated PAR4 inhibition in either a purified system or in whole blood. These results indicate PAR4-specific promotion of platelet granule release and platelet-leukocyte aggregate formation and suggest that pharmacological control of PAR4 activity could potentially attenuate platelet granule release or platelet-leukocyte interaction-mediated pathological processes.
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The role of coagulation and platelets in colon cancer-associated thrombosis.
Mitrugno A, Tassi Yunga S, Sylman JL, Zilberman-Rudenko J, Shirai T, Hebert JF, Kayton R, Zhang Y, Nan X, Shatzel JJ, Esener S, Duvernay MT, Hamm HE, Gruber A, Williams CD, Takata Y, Armstrong R, Morgan TK, McCarty OJT
(2019) Am J Physiol Cell Physiol 316: C264-C273
MeSH Terms: Blood Coagulation, Blood Platelets, Cell Line, Tumor, Colonic Neoplasms, Cross-Sectional Studies, Humans, Retrospective Studies, Thrombosis
Show Abstract · Added March 24, 2020
Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.
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Platelet-Based Drug Delivery for Cancer Applications.
Ortiz-Otero N, Mohamed Z, King MR
(2018) Adv Exp Med Biol 1092: 235-251
MeSH Terms: Blood Platelets, Drug Delivery Systems, Hemostasis, Humans, Male, Neoplasm Metastasis, Neoplasms
Show Abstract · Added April 15, 2019
Platelets can be considered as the "guardian of hemostasis" where their main function is to maintain vascular integrity. In pathological conditions, the hemostatic role of platelets may be hijacked to stimulate disease progression. In 1865, Armand Trousseau was a pioneer in establishing the platelet-cancer metastasis relationship, which he eventually termed as Trousseau's Syndrome to describe the deregulation of the hemostasis-associated pathways induced by cancer progression (Varki, Blood. 110(6):1723-9, 2007). Since these early studies, there has been an increase in experimental evidence not only to elucidate the role of platelets in cancer metastasis but also to create novel cancer therapies by targeting the platelet's impact in metastasis. In this chapter, we discuss the contribution of platelets in facilitating tumor cell transit from the primary tumor to distant metastatic sites as well as novel cancer therapies based on platelet interactions.
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7 MeSH Terms
Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets.
Duvernay MT, Temple KJ, Maeng JG, Blobaum AL, Stauffer SR, Lindsley CW, Hamm HE
(2017) Mol Pharmacol 91: 39-47
MeSH Terms: Blood Platelets, Humans, Integrin beta3, Ligands, Platelet Glycoprotein GPIb-IX Complex, Receptor, PAR-1, Receptors, Thrombin, Signal Transduction, Thrombin
Show Abstract · Added March 24, 2020
Human platelets display a unique dual receptor system for responding to its primary endogenous activator, α-thrombin. Because of the lack of efficacious antagonists, the field has relied on synthetic peptides and pepducins to describe protease-activated receptor PAR1 and PAR4 signaling. The precise contributions of each receptor have not been established in the context of thrombin. We took advantage of newly discovered PAR antagonists to contrast the contribution of PAR1 and PAR4 to thrombin-mediated activation of the platelet fibrin receptor (GPIIbIIIa). PAR1 is required for platelet activation at low but not high concentrations of thrombin, and maximal platelet activation at high concentrations of thrombin requires PAR4. As the concentration of thrombin is increased, PAR1 signaling is quickly overcome by PAR4 signaling, leaving a narrow window of low thrombin concentrations that exclusively engage PAR1. PAR4 antagonism reduces the maximum thrombin response by over 50%. Thus, although the PAR1 response still active at higher concentrations of thrombin, this response is superseded by PAR4. Truncation of a known PAR4 antagonist and identification of the minimum pharmacophore converted the mechanism of inhibition from noncompetitive to competitive, such that the antagonist could be outcompeted by increasing doses of the ligand. Fragments retained efficacy against both soluble and tethered ligands with lower cLogP values and an increased free fraction in plasma. These reversible, competitive compounds represent a route toward potentially safer PAR4 antagonists for clinical utility and the development of tools such as radioligands and positron emission tomography tracers that are not currently available to the field for this target.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles.
Temple KJ, Duvernay MT, Maeng JG, Blobaum AL, Stauffer SR, Hamm HE, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 5481-5486
MeSH Terms: Blood Platelets, Humans, Platelet Aggregation, Platelet Aggregation Inhibitors, Receptors, Thrombin, Thiadiazoles, Thrombin
Show Abstract · Added March 24, 2020
This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor.
Oliver KH, Duvernay MT, Hamm HE, Carneiro AM
(2016) J Biol Chem 291: 20210-9
MeSH Terms: Adenosine Diphosphate, Animals, Blood Platelets, Citalopram, Female, Male, Mice, Mice, Knockout, Platelet Glycoprotein GPIIb-IIIa Complex, Receptor, Serotonin, 5-HT2A, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added October 26, 2016
Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERT(-/-)) of SERT function in vivo led to reduced serotonin (5-hydroxytryptamine (5-HT)) blood levels that paralleled a mild bleeding phenotype in mice. Transfusion of wild-type platelets to SERT(-/-) mice normalized bleeding times to wild-type levels, suggesting that loss of SERTs causes a deficiency in platelet activation. Although SERT(-/-) platelets displayed no difference in P-selectin or αIIbβ3 activation upon stimulation with thrombin, ADP-mediated αIIbβ3 activation is reduced in SERT(-/-) platelets. Additionally, synergistic potentiation of αIIbβ3 activation by ADP and 5-HT is lost in SERT(-/-) platelets. Acute treatment of wild-type platelets with 5-HT2A receptor (5-HT2AR) antagonists or SSRIs revealed that functional 5-HT2ARs, not SERTs, are necessary for the synergistic activation of αIIbβ3 by dual 5-HT/ADP stimulation. Pharmacological studies using radiolabeled guanosine 5'-3-O-([(35)S]thio)triphosphate and [(3)H]ketanserin revealed that platelets isolated from SERT(-/-) or citalopram-treated mice have reduced activation of G-proteins coupled to 5-HT2ARs and receptor surface expression. Taken together, these data demonstrate that sustained SERT loss of function reduces 5-HT2AR surface expression that is critical for the synergistic activation of αIIbβ3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated αIIbβ3 activation.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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11 MeSH Terms
Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.
Eicher JD, Chami N, Kacprowski T, Nomura A, Chen MH, Yanek LR, Tajuddin SM, Schick UM, Slater AJ, Pankratz N, Polfus L, Schurmann C, Giri A, Brody JA, Lange LA, Manichaikul A, Hill WD, Pazoki R, Elliot P, Evangelou E, Tzoulaki I, Gao H, Vergnaud AC, Mathias RA, Becker DM, Becker LC, Burt A, Crosslin DR, Lyytikäinen LP, Nikus K, Hernesniemi J, Kähönen M, Raitoharju E, Mononen N, Raitakari OT, Lehtimäki T, Cushman M, Zakai NA, Nickerson DA, Raffield LM, Quarells R, Willer CJ, Peloso GM, Abecasis GR, Liu DJ, Global Lipids Genetics Consortium, Deloukas P, Samani NJ, Schunkert H, Erdmann J, CARDIoGRAM Exome Consortium, Myocardial Infarction Genetics Consortium, Fornage M, Richard M, Tardif JC, Rioux JD, Dube MP, de Denus S, Lu Y, Bottinger EP, Loos RJ, Smith AV, Harris TB, Launer LJ, Gudnason V, Velez Edwards DR, Torstenson ES, Liu Y, Tracy RP, Rotter JI, Rich SS, Highland HM, Boerwinkle E, Li J, Lange E, Wilson JG, Mihailov E, Mägi R, Hirschhorn J, Metspalu A, Esko T, Vacchi-Suzzi C, Nalls MA, Zonderman AB, Evans MK, Engström G, Orho-Melander M, Melander O, O'Donoghue ML, Waterworth DM, Wallentin L, White HD, Floyd JS, Bartz TM, Rice KM, Psaty BM, Starr JM, Liewald DC, Hayward C, Deary IJ, Greinacher A, Völker U, Thiele T, Völzke H, van Rooij FJ, Uitterlinden AG, Franco OH, Dehghan A, Edwards TL, Ganesh SK, Kathiresan S, Faraday N, Auer PL, Reiner AP, Lettre G, Johnson AD
(2016) Am J Hum Genet 99: 40-55
MeSH Terms: Blood Platelets, Exome, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Mean Platelet Volume, Platelet Count
Show Abstract · Added April 26, 2017
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Published by Elsevier Inc.
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9 MeSH Terms
Activated tumor cell integrin αvβ3 cooperates with platelets to promote extravasation and metastasis from the blood stream.
Weber MR, Zuka M, Lorger M, Tschan M, Torbett BE, Zijlstra A, Quigley JP, Staflin K, Eliceiri BP, Krueger JS, Marchese P, Ruggeri ZM, Felding BH
(2016) Thromb Res 140 Suppl 1: S27-36
MeSH Terms: Animals, Blood Platelets, Cell Line, Tumor, Cell Movement, Humans, Integrin alphaVbeta3, Mice, SCID, Neoplasm Metastasis, Neoplastic Cells, Circulating
Show Abstract · Added April 6, 2017
Metastasis is the main cause of death in cancer patients, and understanding mechanisms that control tumor cell dissemination may lead to improved therapy. Tumor cell adhesion receptors contribute to cancer spreading. We noted earlier that tumor cells can expressing the adhesion receptor integrin αvβ3 in distinct states of activation, and found that cells which metastasize from the blood stream express it in a constitutively high affinity form. Here, we analyzed steps of the metastatic cascade in vivo and asked, when and how the affinity state of integrin αvβ3 confers a critical advantage to cancer spreading. Following tumor cells by real time PCR, non-invasive bioluminescence imaging, intravital microscopy and histology allowed us to identify tumor cell extravasation from the blood stream as a rate-limiting step supported by high affinity αvβ3. Successful transendothelial migration depended on cooperation between tumor cells and platelets involving the high affinity tumor cell integrin and release of platelet granules. Thus, this study identifies the high affinity conformer of integrin αvβ3 and its interaction with platelets as critical for early steps during hematogenous metastasis and target for prevention of metastatic disease.
© 2016 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
Structural Basis for Sialoglycan Binding by the Streptococcus sanguinis SrpA Adhesin.
Bensing BA, Loukachevitch LV, McCulloch KM, Yu H, Vann KR, Wawrzak Z, Anderson S, Chen X, Sullam PM, Iverson TM
(2016) J Biol Chem 291: 7230-40
MeSH Terms: Adhesins, Bacterial, Binding Sites, Blood Platelets, Endocarditis, Humans, N-Acetylneuraminic Acid, Streptococcal Infections, Streptococcus, Virulence Factors
Show Abstract · Added April 1, 2019
Streptococcus sanguinisis a leading cause of infective endocarditis, a life-threatening infection of the cardiovascular system. An important interaction in the pathogenesis of infective endocarditis is attachment of the organisms to host platelets.S. sanguinisexpresses a serine-rich repeat adhesin, SrpA, similar in sequence to platelet-binding adhesins associated with increased virulence in this disease. In this study, we determined the first crystal structure of the putative binding region of SrpA (SrpABR) both unliganded and in complex with a synthetic disaccharide ligand at 1.8 and 2.0 Å resolution, respectively. We identified a conserved Thr-Arg motif that orients the sialic acid moiety and is required for binding to platelet monolayers. Furthermore, we propose that sequence insertions in closely related family members contribute to the modulation of structural and functional properties, including the quaternary structure, the tertiary structure, and the ligand-binding site.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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Platelet Lipidomic Profiling: Novel Insight into Cytosolic Phospholipase A2α Activity and Its Role in Human Platelet Activation.
Duvernay MT, Matafonov A, Lindsley CW, Hamm HE
(2015) Biochemistry 54: 5578-88
MeSH Terms: Benzoates, Blood Platelets, Glycerophospholipids, Group IV Phospholipases A2, Humans, Lipids, Oligopeptides, Peptide Fragments, Platelet Activation, Platelet Membrane Glycoproteins, Receptor, PAR-1, Receptors, Thrombin, Spectrometry, Mass, Electrospray Ionization, Stress, Mechanical, Sulfonamides, Thrombin
Show Abstract · Added March 24, 2020
With a newer, more selective and efficacious cytosolic phospholipase A2α (cPLA2α) inhibitor available, we revisited the role of cPLA2α activity in platelet activation and discovered that a component of platelet signaling, even larger than previously appreciated, relies on this enzyme. In a whole blood shear-based flow chamber assay, giripladib, a cPLA2α inhibitor, reduced platelet adhesion and accumulation on collagen. Moreover, giripladib differentially affected P-selectin expression and GPIIbIIIa activation depending on the agonist employed. While protease-activated receptor 1 (PAR1)-mediated platelet activation was unaffected by giripladib, the levels of PAR4- and GPVI-mediated platelet activation were significantly reduced. Meanwhile, the thromboxane A2 receptor antagonist SQ29548 had no effect on PAR-, GPVI-, or puriniergic receptor-mediated platelet activation, suggesting that another eicosanoid produced downstream of arachidonic acid liberation by cPLA2α was responsible for this large component of PAR4- and GPVI-mediated platelet activation. In parallel, we profiled PAR-mediated changes in glycerophospholipid (GPL) mass with and without giripladib to better understand cPLA2α-mediated lipid metabolism. Phosphatidylcholine and phosphatidylethanolamine (PE) demonstrated the largest consumption of mass during thrombin stimulation. Additionally, we confirm phosphatidylinositol as a major substrate of cPLA2α. A comparison of PAR1- and PAR4-induced metabolism revealed the consumption of more putative arachidonyl-PE species downstream of PAR1 activation. Instead of enhanced cPLA2α activity and therefore more arachidonic acid liberation downstream of PAR4, these results indicate the major role that cPLA2α activity plays in platelet function and suggest that a novel eicosanoid is produced in response to platelet activation that represents a large component of PAR4- and GPVI-mediated responses.
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