Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets
Department of Pediatrics
Medical Subject Headings
Androstadienes; Blood 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
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.
Rights and Permissions
Citation: J Biol Chem. 1999 May 14;274(20):14368-75. doi 10.1074/jbc.274.20.14368
Pigazzi, Alessio; Heydrick, Stanley; Folli, Franco; Benoit, Stephen E.; Michelson, Alan D.; and Loscalzo, Joseph, "Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets" (1999). Hematology/Oncology. 16.