Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets
Authors
Pigazzi, AlessioHeydrick, Stanley
Folli, Franco
Benoit, Stephen E.
Michelson, Alan D.
Loscalzo, Joseph
UMass Chan Affiliations
Department of PediatricsDocument Type
Journal ArticlePublication Date
1999-05-14Keywords
AndrostadienesBlood Platelets
Cells, Cultured
Glutathione
Humans
Nitric Oxide
Peptide Fragments
Phosphatidylinositol 3-Kinases
Platelet Aggregation
Platelet Aggregation Inhibitors
Receptors, Thrombin
src-Family Kinases
Hematology
Oncology
Pediatrics
Metadata
Show full item recordAbstract
Although nitric oxide (NO) has potent antiplatelet actions, the signaling pathways affected by NO in the platelet are poorly understood. Since NO can induce platelet disaggregation and phosphoinositide 3-kinase (PI3-kinase) activation renders aggregation irreversible, we tested the hypothesis that NO exerts its antiplatelet effects at least in part by inhibiting PI3-kinase. The results demonstrate that the NO donor S-nitrosoglutathione (S-NO-glutathione) inhibits the stimulation of PI3-kinase associated with tyrosine-phosphorylated proteins and of p85/PI3-kinase associated with the SRC family kinase member LYN following the exposure of platelets to thrombin receptor-activating peptide. The activation of LYN-associated PI3-kinase was unrelated to changes in the amount of PI3-kinase physically associated with LYN signaling complexes but did require the activation of LYN and other tyrosine kinases. The cyclic GMP-dependent kinase activator 8-bromo-cyclic GMP had similar effects on PI3-kinase activity, consistent with a model in which the cyclic nucleotide mediates the effects of NO. Additional studies showed that wortmannin and S-NO-glutathione have additive inhibitory effects on thrombin receptor-activating peptide-induced platelet aggregation and the surface expression of platelet activation markers. These data provide evidence of a distinct and novel mechanism for the inhibitory effects of NO on platelet function.Source
J Biol Chem. 1999 May 14;274(20):14368-75. doi 10.1074/jbc.274.20.14368DOI
10.1074/jbc.274.20.14368Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43337PubMed ID
10318860Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.274.20.14368