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 p110 alpha isoform in IGF-1-mediated enhancement of platelet function. Approach and Results-Using a platelet-specific p110 alpha knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110 alpha, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1-mediated Akt phosphorylation. The p110 beta inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110 alpha-deficient platelets, demonstrating that both p110 alpha and p110 beta contribute to IGF-1-mediated Akt phosphorylation. Genetic deletion of p110 alpha had no effect on IGF-1-mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4-mediated integrin activation and a-granule secretion. In contrast, pharmacological inhibition of p110 alpha blocked IGF-1-mediated potentiation of integrin activation and a-granule secretion. Functional enhancement by IGF-1 in p110 alpha knockout samples was lost after TGX-221 treatment, suggesting that p110 beta drives priming in the absence of the p110 alpha isoform. Conclusions-Together, these results demonstrate that both p110 alpha and p110 beta are involved in Akt signaling by IGF-1, but that it is the p110 alpha isoform that is responsible for IGF-1-mediated potentiation of platelet function.
