Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets

Alessio Pigazzi, Stanley Heydrick, Franco Folli, Stephen Benoit, Alan Michelson, Joseph Loscalzo

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)14368-14375
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number20
DOIs
StatePublished - May 14 1999
Externally publishedYes

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thrombin receptor peptide SFLLRNP
1-Phosphatidylinositol 4-Kinase
Platelets
Phosphatidylinositols
Human Activities
Nitric Oxide
Phosphotransferases
Blood Platelets
S-Nitrosoglutathione
Chemical activation
Guanylate Kinases
Agglomeration
Nitric Oxide Donors
Cyclic Nucleotides
Cyclic GMP
Platelet Activation
Platelet Aggregation
Protein-Tyrosine Kinases
Tyrosine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets. / Pigazzi, Alessio; Heydrick, Stanley; Folli, Franco; Benoit, Stephen; Michelson, Alan; Loscalzo, Joseph.

In: Journal of Biological Chemistry, Vol. 274, No. 20, 14.05.1999, p. 14368-14375.

Research output: Contribution to journalArticle

Pigazzi, Alessio ; Heydrick, Stanley ; Folli, Franco ; Benoit, Stephen ; Michelson, Alan ; Loscalzo, Joseph. / Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 20. pp. 14368-14375.
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