Phosphoinositide 3-kinases p110α and p110β have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming.

Autor:	Blair TA; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.)., Moore SF; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.)., Williams CM; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.)., Poole AW; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.)., Vanhaesebroeck B; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.)., Hers I; From the School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.A.B., S.F.M., C.M.W., A.W.P., I.H.); and Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom (B.V.). i.hers@bristol.ac.uk.
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2014 Aug; Vol. 34 (8), pp. 1681-8. Date of Electronic Publication: 2014 Jun 05.
DOI:	10.1161/ATVBAHA.114.303954
Abstrakt:	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 and Results: 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 p110β inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110α-deficient platelets, demonstrating that both p110α and p110β 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 p110β drives priming in the absence of the p110α isoform. Conclusions: Together, these results demonstrate that both p110α and p110β 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. (© 2014 American Heart Association, Inc.)
Databáze:	MEDLINE
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