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Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation.
Kirkby NS, Reed DM, Edin ML, Rauzi F, Mataragka S, Vojnovic I, Bishop-Bailey D, Milne GL, Longhurst H, Zeldin DC, Mitchell JA, Warner TD
(2015) FASEB J 29: 4568-78
MeSH Terms: Adult, Antigens, Human Platelet, Blood Platelets, Dinoprostone, Endothelial Cells, Epoprostenol, Female, Humans, Leukocytes, Male, Mutation, Platelet Activation
Show Abstract · Added March 10, 2016
Eicosanoids are important vascular regulators, but the phospholipase A2 (PLA2) isoforms supporting their production within the cardiovascular system are not fully understood. To address this, we have studied platelets, endothelial cells, and leukocytes from 2 siblings with a homozygous loss-of-function mutation in group IVA cytosolic phospholipase A2 (cPLA2α). Chromatography/mass spectrometry was used to determine levels of a broad range of eicosanoids produced by isolated vascular cells, and in plasma and urine. Eicosanoid release data were paired with studies of cellular function. Absence of cPLA2α almost abolished eicosanoid synthesis in platelets (e.g., thromboxane A2, control 20.5 ± 1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes [e.g., prostaglandin E2 (PGE2), control 21.9 ± 7.4 ng/ml vs. patient 1.9 ng/ml], and this was associated with impaired platelet activation and enhanced inflammatory responses. cPLA2α-deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I2 (prostacyclin; control 956 ± 422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation. In the urine, prostaglandin metabolites were selectively influenced by cPLA2α deficiency. For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA2α, whereas PGE2 metabolites (77.8% of control) were similar to healthy volunteer levels. These studies constitute a definitive account, demonstrating the fundamental role of cPLA2α to eicosanoid formation and cellular responses within the human circulation.
© FASEB.
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12 MeSH Terms
Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans.
Joy NG, Tate DB, Younk LM, Davis SN
(2015) Diabetes 64: 2571-80
MeSH Terms: Adult, Biomarkers, Blood Glucose, Endothelium, Vascular, Female, Fibrinolysis, Humans, Hypoglycemia, Inflammation, Male, Platelet Activation, Thrombosis
Show Abstract · Added July 30, 2015
The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-α, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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12 MeSH Terms
Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.
Dong J, Dong J, Lin J, Wang B, He S, Wu C, Kushwaha KK, Mohabeer N, Su Y, Fang H, Huang K, Li D
(2015) Cell Physiol Biochem 35: 160-74
MeSH Terms: Androstadienes, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Chromones, Cytokines, Disease Models, Animal, Ferric Compounds, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, P-Selectin, Phosphatidylinositol 3-Kinases, Phosphorylation, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, Signal Transduction, Wortmannin
Show Abstract · Added January 20, 2015
AIMS - Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway.
METHODS AND RESULTS - Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor.
CONCLUSION - This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.
© 2015 S. Karger AG, Basel.
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25 MeSH Terms
α2β1 integrin, GPVI receptor, and common FcRγ chain on mouse platelets mediate distinct responses to collagen in models of thrombosis.
Marjoram RJ, Li Z, He L, Tollefsen DM, Kunicki TJ, Dickeson SK, Santoro SA, Zutter MM
(2014) PLoS One 9: e114035
MeSH Terms: Animals, Blood Platelets, Collagen, Disease Models, Animal, Integrin alpha2beta1, Mice, Mice, Knockout, Platelet Activation, Platelet Membrane Glycoproteins, Rats, Receptors, IgG, Thrombosis
Show Abstract · Added February 12, 2015
OBJECTIVE - Platelets express the α2β1 integrin and the glycoprotein VI (GPVI)/FcRγ complex, both collagen receptors. Understanding platelet-collagen receptor function has been enhanced through use of genetically modified mouse models. Previous studies of GPVI/FcRγ-mediated collagen-induced platelet activation were perfomed with mice in which the FcRγ subunit was genetically deleted (FcRγ-/-) or the complex was depleted. The development of α2β1-/- and GPVI-/- mice permits side-by-side comparison to address contributions of these collagen receptors in vivo and in vitro.
APPROACH AND RESULTS - To understand the different roles played by the α2β1 integrin, the GPVI receptor or FcRγ subunit in collagen-stimulated hemostasis and thrombosis, we compared α2β1-/-, FcRγ-/-, and GPVI-/- mice in models of endothelial injury and intravascular thrombosis in vivo and their platelets in collagen-stimulated activation in vitro. We demonstrate that both the α2β1 integrin and the GPVI receptor, but not the FcRγ subunit influence carotid artery occlusion in vivo. In contrast, the GPVI receptor and the FcRγ chain, but not the α2β1 integrin, play similar roles in intravascular thrombosis in response to soluble Type I collagen. FcRγ-/- platelets showed less attenuation of tyrosine phosphorylation of several proteins including RhoGDI when compared to GPVI-/- and wild type platelets. The difference between FcRγ-/- and GPVI-/- platelet phosphotyrosine levels correlated with the in vivo thrombosis findings.
CONCLUSION - Our data demonstrate that genetic deletion of GPVI receptor, FcRγ chain, or the α2β1 integrin changes the thrombotic potentials of these platelets to collagen dependent on the stimulus mechanism. The data suggest that the FcRγ chain may provide a dominant negative effect through modulating signaling pathways in platelets involving several tyrosine phosphorylated proteins such as RhoGDI. In addition, these findings suggest a more complex signaling network downstream of the platelet collagen receptors than previously appreciated.
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12 MeSH Terms
Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation.
Aldrovandi M, Hammond VJ, Podmore H, Hornshaw M, Clark SR, Marnett LJ, Slatter DA, Murphy RC, Collins PW, O'Donnell VB
(2013) J Lipid Res 54: 3085-97
MeSH Terms: Aspirin, Blood Platelets, Calcium, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Dinoprostone, Dose-Response Relationship, Drug, Esterification, Feedback, Physiological, Humans, Intracellular Space, MAP Kinase Kinase 1, Phosphatidylethanolamines, Phospholipids, Platelet Activation, Prostaglandin D2, Prostaglandins, Protein Kinase C, Receptor, PAR-1, Thrombin, src-Family Kinases
Show Abstract · Added March 7, 2014
Oxidized phospholipids (oxPLs) generated nonenzymatically display pleiotropic biological actions in inflammation. Their generation by cellular cyclooxygenases (COXs) is currently unknown. To determine whether platelets generate prostaglandin (PG)-containing oxPLs, then characterize their structures and mechanisms of formation, we applied precursor scanning-tandem mass spectrometry to lipid extracts of agonist-activated human platelets. Thrombin, collagen, or ionophore activation stimulated generation of families of PGs comprising PGE₂ and D₂ attached to four phosphatidylethanolamine (PE) phospholipids (16:0p/, 18:1p/, 18:0p/, and 18:0a/). They formed within 2 to 5 min of activation in a calcium, phospholipase C, p38 MAP kinases, MEK1, cPLA₂, and src tyrosine kinase-dependent manner (28.1 ± 2.3 pg/2 × 10⁸ platelets). Unlike free PGs, they remained cell associated, suggesting an autocrine mode of action. Their generation was inhibited by in vivo aspirin supplementation (75 mg/day) or in vitro COX-1 blockade. Inhibitors of fatty acyl reesterification blocked generation significantly, while purified COX-1 was unable to directly oxidize PE in vitro. This indicates that they form in platelets via rapid esterification of COX-1 derived PGE₂/D₂ into PE. In summary, COX-1 in human platelets acutely mediates membrane phospholipid oxidation via formation of PG-esterified PLs in response to pathophysiological agonists.
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21 MeSH Terms
12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
Yeung J, Apopa PL, Vesci J, Stolla M, Rai G, Simeonov A, Jadhav A, Fernandez-Perez P, Maloney DJ, Boutaud O, Holman TR, Holinstat M
(2013) Thromb Haemost 110: 569-81
MeSH Terms: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, Animals, Arachidonate 12-Lipoxygenase, Blood Platelets, Cyclooxygenase 1, Eicosanoids, Flow Cytometry, Humans, Mice, Mice, Transgenic, Platelet Activation, Platelet Adhesiveness, Platelet Aggregation, Platelet Membrane Glycoproteins, Receptors, Thrombin, Thrombosis, Time Factors
Show Abstract · Added March 27, 2014
Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.
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17 MeSH Terms
Synthesis of indole derived protease-activated receptor 4 antagonists and characterization in human platelets.
Young SE, Duvernay MT, Schulte ML, Lindsley CW, Hamm HE
(2013) PLoS One 8: e65528
MeSH Terms: Adult, Blood Platelets, Female, Fibrinolytic Agents, Humans, Indazoles, Indoles, Male, Platelet Activation, Receptors, Thrombin
Show Abstract · Added December 10, 2013
Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a novel series of indole-based PAR4 antagonists also necessitated the development of a platelet based high-throughput screening assay. Screening and subsequent structure activity relationship analysis yielded several selective PAR4 antagonists as well as possible new scaffolds for future antagonist development.
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10 MeSH Terms
Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice.
Huttinger ZM, Milks MW, Nickoli MS, Aurand WL, Long LC, Wheeler DG, Dwyer KM, d'Apice AJ, Robson SC, Cowan PJ, Gumina RJ
(2012) Am J Pathol 181: 322-33
MeSH Terms: Adenosine, Animals, Antigens, CD, Apyrase, Carotid Artery Thrombosis, Cells, Cultured, Chlorides, Ferric Compounds, Mice, Mice, Transgenic, Platelet Activation, Platelet Aggregation, Receptors, Purinergic P2, Signal Transduction
Show Abstract · Added February 21, 2015
Modulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/β(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Protein kinase C regulation of 12-lipoxygenase-mediated human platelet activation.
Yeung J, Apopa PL, Vesci J, Kenyon V, Rai G, Jadhav A, Simeonov A, Holman TR, Maloney DJ, Boutaud O, Holinstat M
(2012) Mol Pharmacol 81: 420-30
MeSH Terms: Arachidonate 12-Lipoxygenase, Blood Platelets, Blotting, Western, Calcium, Enzyme Activation, Flow Cytometry, Gas Chromatography-Mass Spectrometry, Humans, Lipoxygenase Inhibitors, Platelet Activation, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Kinase C, Protein Kinase Inhibitors
Show Abstract · Added March 27, 2014
Platelet activation is important in the regulation of hemostasis and thrombosis. Uncontrolled activation of platelets may lead to arterial thrombosis, which is a major cause of myocardial infarction and stroke. After activation, metabolism of arachidonic acid (AA) by 12-lipoxygenase (12-LOX) may play a significant role in regulating the degree and stability of platelet activation because inhibition of 12-LOX significantly attenuates platelet aggregation in response to various agonists. Protein kinase C (PKC) activation is also known to be an important regulator of platelet activity. Using a newly developed selective inhibitor for 12-LOX and a pan-PKC inhibitor, we investigated the role of PKC in 12-LOX-mediated regulation of agonist signaling in the platelet. To determine the role of PKC within the 12-LOX pathway, a number of biochemical endpoints were measured, including platelet aggregation, calcium mobilization, and integrin activation. Inhibition of 12-LOX or PKC resulted in inhibition of dense granule secretion and attenuation of both aggregation and αIIbβ(3) activation. However, activation of PKC downstream of 12-LOX inhibition rescued agonist-induced aggregation and integrin activation. Furthermore, inhibition of 12-LOX had no effect on PKC-mediated aggregation, indicating that 12-LOX is upstream of PKC. These studies support an essential role for PKC downstream of 12-LOX activation in human platelets and suggest 12-LOX as a possible target for antiplatelet therapy.
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13 MeSH Terms
Hemocompatibility of silicon-based substrates for biomedical implant applications.
Muthusubramaniam L, Lowe R, Fissell WH, Li L, Marchant RE, Desai TA, Roy S
(2011) Ann Biomed Eng 39: 1296-305
MeSH Terms: Biocompatible Materials, Biomedical Engineering, Blood Coagulation, Complement Activation, Humans, In Vitro Techniques, Materials Testing, Miniaturization, Platelet Activation, Platelet Adhesiveness, Polytetrafluoroethylene, Prostheses and Implants, Renal Replacement Therapy, Silicon, Stainless Steel, Surface Properties
Show Abstract · Added August 21, 2013
Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories-coagulation (thrombin-antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems.
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16 MeSH Terms