Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets.
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.
Sheu
J R
JR
Graduate Institute of Medical Sciences and Department of Pharmacology, Taipei Medical College, Taiwan. sheujr@tmc.edu.tw
Lee
C R
CR
Lin
C H
CH
Hsiao
G
G
Ko
W C
WC
Chen
Y C
YC
Yen
M H
MH
D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D003094:Collagen / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000097:blood / Q000150:complications / Q000382:microbiology; D004789:Enzyme Activation / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000097:blood / Q000150:complications; D016908:Gram-Positive Bacterial Infections / Q000097:blood / Q000150:complications; D006474:Hemorrhagic Disorders / Q000209:etiology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010455:Peptides / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000150:complications / Q000382:microbiology; D012772:Shock, Septic / Q000097:blood / Q000150:complications; D013211:Staphylococcus aureus / Q000737:chemistry*; D013682:Teichoic Acids / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000096:biosynthesis
D008070:Lipopolysaccharides; D008563:Membrane Lipids; D010455:Peptides; D010716:Phosphatidylinositols; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013682:Teichoic Acids; C070025:triflavin; D015240:Phorbol 12,13-Dibutyrate; D013929:Thromboxane B2; C009900:lipoteichoic acid; D013928:Thromboxane A2; D003094:Collagen; D007770:L-Lactate Dehydrogenase; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C