| First Author | Blair TA | Year | 2014 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 34 |
| Issue | 8 | Pages | 1681-8 |
| PubMed ID | 24903091 | Mgi Jnum | J:227104 |
| Mgi Id | MGI:5699672 | Doi | 10.1161/ATVBAHA.114.303954 |
| Citation | Blair TA, et al. (2014) Phosphoinositide 3-kinases p110alpha and p110beta have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming. Arterioscler Thromb Vasc Biol 34(8):1681-8 |
| abstractText | 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 p110alpha isoform in IGF-1-mediated enhancement of platelet function. APPROACH AND RESULTS: Using a platelet-specific p110alpha knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110alpha, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1-mediated Akt phosphorylation. The p110beta inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110alpha-deficient platelets, demonstrating that both p110alpha and p110beta contribute to IGF-1-mediated Akt phosphorylation. Genetic deletion of p110alpha had no effect on IGF-1-mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4-mediated integrin activation and alpha-granule secretion. In contrast, pharmacological inhibition of p110alpha blocked IGF-1-mediated potentiation of integrin activation and alpha-granule secretion. Functional enhancement by IGF-1 in p110alpha knockout samples was lost after TGX-221 treatment, suggesting that p110beta drives priming in the absence of the p110alpha isoform. CONCLUSIONS: Together, these results demonstrate that both p110alpha and p110beta are involved in Akt signaling by IGF-1, but that it is the p110alpha isoform that is responsible for IGF-1-mediated potentiation of platelet function. |
