scholarly journals Oxidized LDL activates blood platelets through CD36/NOX2–mediated inhibition of the cGMP/protein kinase G signaling cascade

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2693-2703 ◽  
Author(s):  
Simbarashe Magwenzi ◽  
Casey Woodward ◽  
Katie S. Wraith ◽  
Ahmed Aburima ◽  
Zaher Raslan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Oxidized Ldl ◽  
Protein Kinase G ◽  
Signaling Cascade ◽  
Key Points ◽  
Cgmp Signaling

Key Points oxLDL binds platelet CD36 to stimulate tyrosine kinase– and PKC-dependent activation of NOX2 and generation of ROS. oxLDL- and hyperlipidemia-induced ROS mediate platelet desensitization to inhibitory cGMP signaling to facilitate platelet activation and thrombus formation.

scholarly journals Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1823-1830 ◽  
Author(s):  
Benoit Decouture ◽  
Elise Dreano ◽  
Tiphaine Belleville-Rolland ◽  
Orjeta Kuci ◽  
Blandine Dizier ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Key Points ◽  
Platelet Signaling ◽  
Deficient Mice ◽  
Kinase A

Key PointsIn vivo and in vitro thrombus formation is altered in MRP4-deficient mice. MRP4 modulates the cAMP–protein kinase A platelet signaling pathway.

scholarly journals Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Blood ◽  
2018 ◽  
Vol 131 (24) ◽  
pp. 2605-2616 ◽  
Author(s):  
Kristina Busygina ◽  
Janina Jamasbi ◽  
Till Seiler ◽  
Hans Deckmyn ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Atherosclerotic Plaque ◽  
Kinase Inhibitors ◽  
Thrombus Formation ◽  
Drug Dosing ◽  
Key Points ◽  
Bruton Tyrosine Kinase ◽  
Platelet Thrombus ◽  
Btk Inhibitors

Key Points Btk inhibitors specifically block platelet thrombus formation on atherosclerotic plaque but spare physiologic hemostasis. Irreversible Btk inactivation in platelets incapable of enzyme resynthesis allows low intermittent drug dosing for antiatherothrombosis.

scholarly journals Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?

2019 ◽  
Vol 3 (23) ◽  
pp. 4021-4033 ◽  
Author(s):  
Luise Goldmann ◽  
Rundan Duan ◽  
Thorsten Kragh ◽  
Georg Wittmann ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Platelet Activation ◽  
Kinase Inhibitors ◽  
Fc Receptor ◽  
Cross Linking ◽  
Key Points ◽  
Bruton Tyrosine Kinase

Key Points Six different BTKi’s blocked platelet activation in blood after FcγRIIA stimulation by cross-linking, anti-CD9 antibodies, or HIT serum. Established oral irreversible and novel reversible BTKi’s may offer a new option to treat HIT.

scholarly journals Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways

Blood ◽  
2013 ◽  
Vol 122 (4) ◽  
pp. 580-589 ◽  
Author(s):  
Katie S. Wraith ◽  
Simbarashe Magwenzi ◽  
Ahmed Aburima ◽  
Yichuan Wen ◽  
David Leake ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Platelet Activation ◽  
Shape Change ◽  
Oxidized Ldl ◽  
Rapid Change ◽  
Rho Kinase ◽  
Low Density Lipoproteins ◽  
Low Density ◽  
Key Points ◽  
Platelet Shape

Key Points Oxidized LDL stimulates rapid change in platelet shape through ligation of CD36. Ligation of CD36 by oxidized LDL simultaneously activates tyrosine and Rho kinase–dependent signaling pathways.

LPS Stimulates Platelet Secretion and Promotes Platelet Aggregation Via TLR4/MyD88 and the cGMP-Dependent Protein Kinase Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3658-3658
Author(s):  
Guoying Zhang ◽  
Emily Welch ◽  
Asrar B. Malik ◽  
Xiaoping Du ◽  
Zhenyu Li
Keyword(s):  
Platelet Aggregation ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Critical Role ◽  
Atp Release ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Platelet Secretion

Abstract Bacterial lipopolysaccharide (LPS) induces rapid thrombocytopenia, hypotension and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. Here we show that LPS stimulated platelet secretion of dense and alpha granules as indicated by ATP release and P-selectin expression, and thus enhanced platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including Toll-like receptor (TLR4), CD14, MD2, and MyD88. The effect of LPS on platelet activation was abolished by an anti-TLR4 blocking antibody or TLR4 knockout. Furthermore, LPS-induced potentiation of platelet aggregation and FeCl3-induced thrombus formation were abolished in MyD88 knockout mice. Importantly, TLR4 mediates LPS-induced cGMP elevation and the stimulatory effect of LPS on platelet aggregation was also abolished by inhibitors of nitric oxide synthase (NOS) and the cGMP-dependent protein kinase (PKG). Thus, LPS promotes platelet secretion and aggregation through a TLR4/MyD88 and cGMP/PKG-dependent pathway.

scholarly journals Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis

2017 ◽  
Vol 114 (11) ◽  
pp. 2964-2969 ◽  
Author(s):  
Yiwen Zhang ◽  
Jian Zhang ◽  
Rong Yan ◽  
Jingluan Tian ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Critical Role ◽  
In Vivo Model ◽  
Clot Retraction ◽  
Interacting Protein ◽  
Bone Marrow Derived Cells

Previous studies have shown that receptor-interacting protein kinase 3 (RIP3) is involved in many important biological processes, including necroptosis, apoptosis, and inflammation. Here we show that RIP3 plays a critical role in regulating platelet functions and in vivo thrombosis and hemostasis. Tail bleeding times were significantly longer in RIP3-knockout (RIP3−/−) mice compared with their wild-type (WT) littermates. In an in vivo model of arteriole thrombosis, mice lacking RIP3 exhibited prolonged occlusion times. WT mice repopulated with RIP3−/− bone marrow-derived cells had longer occlusion times than RIP3−/− mice repopulated with WT bone marrow-derived cells, suggesting a role for RIP3-deficient platelets in arterial thrombosis. Consistent with these findings, we observed that RIP3 was expressed in both human and mice platelets. Deletion of RIP3 in mouse platelets caused a marked defect in aggregation and attenuated dense granule secretion in response to low doses of thrombin or a thromboxane A2 analog, U46619. Phosphorylation of Akt induced by U46619 or thrombin was diminished in RIP3−/− platelets. Moreover, RIP3 interacted with Gα13. Platelet spreading on fibrinogen and clot retraction were impaired in the absence of RIP3. RIP3 inhibitor dose-dependently inhibited platelet aggregation in vitro and prevented arterial thrombus formation in vivo. These data demonstrate a role for RIP3 in promoting in vivo thrombosis and hemostasis by amplifying platelet activation. RIP3 may represent a novel promising therapeutic target for thrombotic diseases.

The control of blood platelets by cAMP signalling

2014 ◽  
Vol 42 (2) ◽  
pp. 289-294 ◽  
Author(s):  
Zaher Raslan ◽  
Khalid M. Naseem
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Platelet Activation ◽  
Blood Platelets ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
Signalling Pathway ◽  
Current Understanding ◽  
Camp Signalling ◽  
Kinase A

Blood platelet activation must be tightly regulated to ensure a balance between haemostasis and thrombosis. The cAMP signalling pathway is the most powerful endogenous regulator of blood platelet activation. PKA (protein kinase A), the foremost effector of cAMP signalling in platelets, phosphorylates a number of proteins that are thought to modulate multiple aspects of platelet activation. In the present mini-review, we outline our current understanding of cAMP-mediated platelet inhibition and discuss some of the issues that require clarification.

scholarly journals The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation

2021 ◽  
Author(s):  
Leila Revollo ◽  
Glenn Merrill-Skoloff ◽  
Karen De Ceunynck ◽  
James R. Dilks ◽  
Mattia Bordoli ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Secretory Pathway ◽  
Thrombus Formation ◽  
Extracellular Proteins ◽  
Normal Platelet

AbstractTyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate Lonesome Kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet ɑ-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology, but have dramatic changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets demonstrate a significant decrease of several tyrosine phosphobands. Functional testing of VLK-deficient platelets shows decreased PAR4- and collagen-mediated platelet aggregation, but normal responses to ADP. Dense granule and α-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased PAR4-mediated Akt (S473) and Erk1/2(T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets demonstrate strongly reduced platelet accumulation and fibrin formation following laser-injury of cremaster arterioles compared to controls. These studies demonstrate that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.

scholarly journals The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation

Blood ◽  
2021 ◽  
Author(s):  
Leila Denise Revollo ◽  
Glenn Merrill-Skoloff ◽  
Karen De Ceunynck ◽  
James R Dilks ◽  
Shihui Guo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Secretory Pathway ◽  
Thrombus Formation ◽  
Extracellular Proteins ◽  
Normal Platelet

Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate Lonesome Kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet ɑ-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology, but have significant changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets demonstrate a significant decrease of several tyrosine phosphobands. Functional testing of VLK-deficient platelets shows decreased PAR4- and collagen-mediated platelet aggregation, but normal responses to ADP. Dense granule and a-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased PAR4-mediated Akt (S473) and Erk1/2 (T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets demonstrate strongly reduced platelet accumulation and fibrin formation following laser-injury of cremaster arterioles compared to controls, but normal bleeding times. These studies demonstrate that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.

scholarly journals In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function

2017 ◽  
Vol 1 (14) ◽  
pp. 918-932 ◽  
Author(s):  
Tom N. Durrant ◽  
James L. Hutchinson ◽  
Kate J. Heesom ◽  
Karen E. Anderson ◽  
Len R. Stephens ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Function ◽  
Binding Proteins ◽  
Thrombus Formation ◽  
Negative Regulator ◽  
Valuable Resource ◽  
Future Studies ◽  
Glycoprotein Vi ◽  
Key Points ◽  
Depth Analysis

Key Points We present the first in-depth analysis of platelet PtdIns(3,4,5)P3-binding proteins, providing a valuable resource for future studies. The PtdIns(3,4,5)P3-binding protein, DAPP1, negatively regulates glycoprotein VI–driven platelet activation and thrombus formation.

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