Phosphoinositide 3-Kinases p110α and p110β Have Differential Roles in Insulin-Like Growth Factor-1–Mediated Akt Phosphorylation and Platelet Priming
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.
- Received February 2, 2014.
- Accepted May 20, 2014.
- © 2014 American Heart Association, Inc.