Phosphoinositide 3-kinases p110α and p110ß have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming.
Arterioscler Thromb Vasc Biol
; 34(8): 1681-8, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24903091
ABSTRACT
OBJECTIVE:
Platelet hyperactivity is a contributing factor in the pathogenesis of cardiovascular disease and can be induced by elevated levels of circulating growth factors, such as insulin-like growth factor-1 (IGF-1). IGF-1 is a primer that cannot stimulate platelet activation by itself, but in combination with physiological stimuli can potentiate platelet functional responses via a phosphoinositide 3-kinase-dependent mechanism. In this study, we explored the role of the phosphoinositide 3-kinase p110α isoform in IGF-1-mediated enhancement of platelet function. APPROACH ANDRESULTS:
Using a platelet-specific p110α knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110α, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1-mediated Akt phosphorylation. The p110ß inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110α-deficient platelets, demonstrating that both p110α and p110ß contribute to IGF-1-mediated Akt phosphorylation. Genetic deletion of p110α had no effect on IGF-1-mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4-mediated integrin activation and α-granule secretion. In contrast, pharmacological inhibition of p110α blocked IGF-1-mediated potentiation of integrin activation and α-granule secretion. Functional enhancement by IGF-1 in p110α knockout samples was lost after TGX-221 treatment, suggesting that p110ß drives priming in the absence of the p110α isoform.CONCLUSIONS:
Together, these results demonstrate that both p110α and p110ß are involved in Akt signaling by IGF-1, but that it is the p110α isoform that is responsible for IGF-1-mediated potentiation of platelet function.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plaquetas
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Fator de Crescimento Insulin-Like I
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Ativação Plaquetária
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Fosfatidilinositol 3-Quinases
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Proteínas Proto-Oncogênicas c-akt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article