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https://www.readbyqxmd.com/read/28751543/adpase-cd39-fused-to-glycoprotein-vi-fc-boosts-local-antithrombotic-effects-at-vascular-lesions
#1
Heidrun Degen, Oliver Borst, Melanie Ziegler, Ann-Katrin Mojica Munoz, Janina Jamasbi, Britta Walker, Silvia Göbel, Julia Fassbender, Kristin Adler, Richard Brandl, Götz Münch, Reinhard Lorenz, Wolfgang Siess, Meinrad Gawaz, Martin Ungerer
BACKGROUND: GPVI (Glycoprotein VI) is the essential platelet collagen receptor in atherothrombosis. Dimeric GPVI-Fc (Revacept) binds to GPVI binding sites on plaque collagen. As expected, it did not increase bleeding in clinical studies. GPVI-Fc is a potent inhibitor of atherosclerotic plaque-induced platelet aggregation at high shear flow, but its inhibition at low shear flow is limited. We sought to increase the platelet inhibitory potential by fusing GPVI-Fc to the ectonucleotidase CD39 (fusion protein GPVI-CD39), which inhibits local ADP accumulation at vascular plaques, and thus to create a lesion-directed dual antiplatelet therapy that is expected to lack systemic bleeding risks...
July 27, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28742189/novel-endogenous-negative-modulators-of-platelet-function-as-potential-anti-thrombotic-targets
#2
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28727490/comparison-of-the-release-of-micrornas-and-extracellular-vesicles-from-platelets-in-response-to-different-agonists
#3
Ashley R Ambrose, Mohammed A Alsahli, Sameer A Kurmani, Alison H Goodall
On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP...
July 20, 2017: Platelets
https://www.readbyqxmd.com/read/28598382/syk-activity-is-dispensable-for-platelet-gp1b-ix-v-signaling
#4
Rachit Badolia, John C Kostyak, Carol Dangelmaier, Satya P Kunapuli
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation...
June 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28598281/design-development-and-characterization-of-act017-a-humanized-fab-that-blocks-platelet-s-glycoprotein-vi-function-without-causing-bleeding-risks
#5
Kristell Lebozec, Martine Jandrot-Perrus, Gilles Avenard, Olivier Favre-Bulle, Philippe Billiald
Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties...
August 2017: MAbs
https://www.readbyqxmd.com/read/28597906/platelet-receptors-as-therapeutic-targets-past-present-and-future
#6
Janina Jamasbi, Keng Ayabe, Shinya Goto, Bernhard Nieswandt, Karlheinz Peter, Wolfgang Siess
Anti-platelet drugs reduce arterial thrombosis after plaque rupture and erosion, prevent stent thrombosis and are used to prevent and treat myocardial infarction and ischaemic stroke. Some of them may also be helpful in treating less frequent diseases such as thrombotic thrombocytopenic purpura. The present concise review aims to cover current and future developments of anti-platelet drugs interfering with the interaction of von Willebrand factor (VWF) with glycoprotein (GP) Ibα, and directed against GPVI, GPIIb/IIIa (integrin αIIbβ3), the thrombin receptor PAR-1, and the ADP receptor P2Y12...
June 28, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28596377/trowaglerix-venom-polypeptides-as-a-novel-antithrombotic-agent-by-targeting-immunoglobulin-like-domains-of-glycoprotein-vi-in-platelet
#7
Chien-Hsin Chang, Ching-Hu Chung, Yi-Shu Tu, Cheng-Chieh Tsai, Chun-Chieh Hsu, Hui-Chin Peng, Yufeng J Tseng, Tur-Fu Huang
OBJECTIVE: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic. APPROACH AND RESULTS: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix α subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein)...
July 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28569920/recombinant-gpvi-fc-added-to-single-or-dual-antiplatelet-therapy-in-vitro-prevents-plaque-induced-platelet-thrombus-formation
#8
Ann-Katrin Mojica Muñoz, Janina Jamasbi, Kerstin Uhland, Heidrun Degen, Götz Münch, Martin Ungerer, Richard Brandl, Remco Megens, Christian Weber, Reinhard Lorenz, Wolfgang Siess
The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y12 antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque...
August 1, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28536721/differential-integrin-activity-mediated-by-platelet-collagen-receptor-engagement-under-flow-conditions
#9
Nicholas Pugh, Ben D Maddox, Dominique Bihan, Kirk A Taylor, Martyn P Mahaut-Smith, Richard W Farndale
The platelet receptors glycoprotein (Gp)VI, integrin α2β1 and GpIb/V/IX mediate platelet adhesion and activation during thrombogenesis. Increases of intracellular Ca(2+) ([Ca(2+)]i) are key signals during platelet activation; however, their relative importance in coupling different collagen receptors to functional responses under shear conditions remains unclear. To study shear-dependent, receptor-specific platelet responses, we used collagen or combinations of receptor-specific collagen-mimetic peptides as substrates for platelet adhesion and activation in whole human blood under arterial flow conditions and compared real-time and endpoint parameters of thrombus formation alongside [Ca(2+)]i measurements using confocal imaging...
July 26, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28523478/anti-gpvi-fab-sar264565-effectively-blocks-gpvi-function-in-ex-vivo-human-platelets-under-arterial-shear-in-a-perfusion-chamber
#10
Peter Florian, Peter Wonerow, Sebastian Harder, Karina Kuczka, Michel Dubar, Jochen Graff
INTRODUCTION: Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. METHODS: The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow...
August 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28441661/defective-platelet-activation-and-bleeding-complications-upon-cholestasis-in-mice
#11
Nina Sarah Gowert, Meike Klier, Maria Reich, Friedrich Reusswig, Lili Donner, Verena Keitel, Dieter Häussinger, Margitta Elvers
BACKGROUND/AIMS: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. METHODS: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28415757/an-absence-of-platelet-activation-following-thalidomide-treatment-in-vitro-or-in-vivo
#12
Jianlin Qiao, Yulu Wu, Xiaoqing Wu, Yun Liu, Xiaoqian Li, Wen Ju, Kunming Qi, Depeng Li, Elizabeth E Gardiner, Robert K Andrews, Lingyu Zeng, Kailin Xu
Increased risk of thromboembolism and platelet hyperreactivity has been reported in patients receiving thalidomide therapy. Whether thalidomide induces platelet activation directly or through other factors remains unclear. The aim of this study was to evaluate the effect of thalidomide on platelet activation under resting conditions in vitro and in vivo. Isolated human or mouse platelets were treated with different concentrations of thalidomide (10, 50 and 100 μg/ml) for 60 min at 37°C followed by analysis of platelet surface expression of platelet receptors GPIbα, GPVI, αIIbβ3 and P-selectin, and PAC-1 or fibrinogen binding, by flow cytometry and collagen- or ADP-induced platelet aggregation...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404545/doxepin-inhibits-gpvi-dependent-platelet-ca-2-signaling-and-collagen-dependent-thrombus-formation
#13
Sascha Geue, Britta Walker-Allgaier, Daniela Eißler, Roland Tegtmeyer, Malte Schaub, Florian Lang, Meinrad Gawaz, Oliver Borst, Patrick Münzer
Platelet adhesion, activation, and aggregation are essential for primary hemostasis, but are also critically involved in the development of acute arterial thrombotic occlusion. Stimulation of the collagen receptor glycoprotein VI (GPVI) leads to phospholipase Cγ2-dependent inositol triphosphate (IP3) production with subsequent platelet activation, due to increased intracellular Ca(2+) concentration ([Ca(2+)]i). Although tricyclic antidepressants have been shown to potentially impair platelet activation, nothing is hitherto known about potential effects of the tricyclic antidepressant doxepin on platelet Ca(2+) signaling and thrombus formation...
June 1, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28337278/synthesis-of-huaicarbon-a-b-and-their-activating-effects-on-platelet-glycoprotein-vi-receptor-to-mediate-collagen-induced-platelet-aggregation
#14
Hongli Yu, Yeqing Chen, Hao Wu, Kuilong Wang, Liping Liu, Xingde Zhang
Quercetin and rhamnose were efficiently converted into huaicarbon A/B by heating at 250°C for 10-15 min or at 200°C for 25-30 min. With the optimum molar ratio of quercetin/rhamnose (1:3), huaicarbon A and B yields reached 25% and 16% respectively after heating at 250°C, with 55% quercetin conversion. Huaicarbon A/B both promoted washed platelet aggregation dose-dependently, which was antagonized by an inhibitor of glycoprotein VI (GPVI) receptor. Similarly, they both promoted collagen-induced platelet aggregation in platelet-rich plasma in dose-dependent manners...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28283589/tula-2-protein-phosphatase-suppresses-activation-of-syk-through-the-gpvi-platelet-receptor-for-collagen-by-dephosphorylating-tyr-p-346-a-regulatory-site-of-syk
#15
Kevin Reppschläger, Jeanne Gosselin, Carol A Dangelmaier, Dafydd H Thomas, Nick Carpino, Steven E McKenzie, Satya P Kunapuli, Alexander Y Tsygankov
No abstract text is available yet for this article.
March 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28278197/the-role-of-platelet-and-endothelial-garp-in-thrombosis-and-hemostasis
#16
Elien Vermeersch, Frederik Denorme, Wim Maes, Simon F De Meyer, Karen Vanhoorelbeke, Justin Edwards, Ethan M Shevach, Derya Unutmaz, Hodaka Fujii, Hans Deckmyn, Claudia Tersteeg
BACKGROUND: Glycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish. OBJECTIVES: To evaluate the role of GARP in platelet physiology and in thrombus formation using platelet and endothelial conditional GARP knock out mice. METHODS: Platelet and endothelial specific GARP knockout mice were generated using the Cre-loxP recombination system...
2017: PloS One
https://www.readbyqxmd.com/read/28254816/rxr-ligands-negatively-regulate-thrombosis-and-hemostasis
#17
Amanda J Unsworth, Gagan D Flora, Parvathy Sasikumar, Alexander P Bye, Tanya Sage, Neline Kriek, Marilena Crescente, Jonathan M Gibbins
OBJECTIVE: Platelets have been found to express intracellular nuclear receptors including the retinoid X receptors (RXRα and RXRβ). Treatment of platelets with ligands of RXR has been shown to inhibit platelet responses to ADP and thromboxane A2; however, the effects on responses to other platelet agonists and the underlying mechanism have not been fully characterized. APPROACH AND RESULTS: The effect of 9-cis-retinoic acid, docosahexaenoic acid and methoprene acid on collagen receptor (glycoprotein VI [GPVI]) agonists and thrombin-stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilization, integrin αIIbβ3 outside-in signaling and thrombus formation in vitro and in vivo were determined...
May 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28245414/-advances-of-studies-on-platelet-gpvi-as-antithrombotic-target-review
#18
Pan Li, Jian-Lin Qiao, Kai-Lin Xu
Platelet activation is a crucial step in both physiological hemostasis and pathological thrombosis, which is an important mean to prevent and treat thrombotic diseases by inhibition of platelet activation. The current clinical antithrombotic therapy showed a high efficiency, but at risk of bleeding. Platelet glycoprotein VI (GPVI) is a platelet-specific receptor and its binding with collagen is critical for platelet activation. GPVI antagonists were shown to effectively inhibit thrombosis and inflammation without influence on normal hemostasis...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28164654/expression-of-platelet-collagen-receptor-glycoprotein-vi-in-coronary-heart-disease-interaction-between-platelets-and-endothelial-cells
#19
Jian Shi, Ning Zhu, Jiwen Wang, Yu Wang, Zhaohong Geng, Suya Gao, Zhongyan Li
BACKGROUND: 1) To investigate the expression of platelet collagen receptor glycoprotein VI (GPVI) on the surface of platelets in patients with coronary heart disease (CHD). 2) To investigate the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells after exposure to subjects' platelets. METHODS: Platelets were extracted from blood samples of 97 subjects including 43 with acute coronary syndrome (ACS), 21 with stable angina pectoris (SAP), and 33 serving as controls in which CHD was excluded...
July 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28155721/computer-prediction-of-paratope-on-antithrombotic-antibody-10b12-and-epitope-on-platelet-glycoprotein-vi-via-molecular-dynamics-simulation
#20
Wenping Liu, Guangjian Liu, Huiyun Zhou, Xiang Fang, Ying Fang, Jianhua Wu
BACKGROUND: Interaction between immunoglobulin-like receptor glycoprotein VI (GPVI) and collagen plays a central role in platelet activation and sequent firm adhesion. Of various antithrombotic agents targeting GPVI, antibody 10B12 is of great potential to block the GPVI-collagen interaction, but less is known about 10B12 paratope and GPVI epitope. METHODS: Along the pathway in the computer strategy presented in our previous work, the 10B12/GPVI complex model was constructed through homology modeling and rigid-body docking, and the molecular dynamics (MD) simulation was used to detect the paratope residues on 10B12 and their partners on GPVI...
December 28, 2016: Biomedical Engineering Online
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