Abstract
In this study, gram-positive Staphylococcus aureus lipoteichoic acid (LTA) dose-dependently (0.1-1.0 microg/ml) and time-dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists. LTA also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. LTA (0.5 and 1.0 microg/ml) also significantly inhibited thromboxane A2 formation stimulated by collagen in human platelets. Moreover, LTA (0.1-1.0 microg/ml) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatrience. Rapid phosphorylation of a platelet protein of Mr. 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (30 nM). This phosphorylation was markedly inhibited by LTA (0.5 and 1.0 microg/ml) within a 10-min incubation period. These results indicate that the antiplatelet activity of LTA may be involved in the following pathways: LTA's effects may initially be due to induction of conformational changes in the platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca+2 mobilization and phosphorylation of P47 protein. Therefore, LTA-mediated alteration of platelet function may contribute to bleeding diathesis in gram-positive septicemic and endotoxemic patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium Signaling / drug effects
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Cell Membrane / drug effects
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Cell Membrane / ultrastructure
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Collagen / pharmacology
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Cytosol / enzymology
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Dose-Response Relationship, Drug
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Endotoxemia / blood
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Endotoxemia / complications
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Endotoxemia / microbiology
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Enzyme Activation / drug effects
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Gram-Negative Bacterial Infections / blood
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Gram-Negative Bacterial Infections / complications
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Gram-Positive Bacterial Infections / blood
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Gram-Positive Bacterial Infections / complications
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Hemorrhagic Disorders / etiology
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Humans
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L-Lactate Dehydrogenase / analysis
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Lipopolysaccharides / pharmacology*
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Membrane Fluidity / drug effects
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Membrane Lipids / metabolism
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Peptides / pharmacology
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Phorbol 12,13-Dibutyrate / pharmacology
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Phosphatidylinositols / metabolism
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Phosphorylation / drug effects
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Platelet Aggregation / drug effects*
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Platelet Aggregation Inhibitors / pharmacology*
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Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Processing, Post-Translational / drug effects
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Sepsis / blood
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Sepsis / complications
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Sepsis / microbiology
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Shock, Septic / blood
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Shock, Septic / complications
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Staphylococcus aureus / chemistry*
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Teichoic Acids / pharmacology*
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Thromboxane A2 / biosynthesis
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Thromboxane B2 / biosynthesis
Substances
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Lipopolysaccharides
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Membrane Lipids
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Peptides
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Phosphatidylinositols
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Platelet Aggregation Inhibitors
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Platelet Glycoprotein GPIIb-IIIa Complex
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Teichoic Acids
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triflavin
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Phorbol 12,13-Dibutyrate
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Thromboxane B2
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lipoteichoic acid
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Thromboxane A2
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Collagen
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L-Lactate Dehydrogenase
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Protein Kinase C