Aims Phosphatidylinositol 3 kinases (PI3Ks) play a pivotal role in vascular physiology and pathophysiology.We aimed to investigate the role of p55γ, a regulatory subunit of PI3Ks, in vascular smooth muscle cell (VSMC) proliferation and neointimal formation. Methods and results We identified p55γ as an important factor that suppresses VSMC proliferation and injury-evoked neointimal formation. Western blot and mRNA analyses showed that p55γ expression declined in balloon-injured rat carotid arteries and in response to PDGF-BB and serum treatment in cultured VSMCs. Overexpression of p55γ inhibited, whereas short hairpin RNA knockdown of p55γ promoted PDGF-BB- and serum-induced VSMC proliferation. Importantly, in vivo adenoviral gene transfer of p55γ into carotid arteries attenuated, while knockdown of p55γ enhanced balloon injuryinduced neointimal formation. Furthermore, p55γ sequentially up-regulated p53 and p21, resulting in cell-cycle arrest in S phase; small-interfering RNA knockdown of either p53 or p21 blocked p55γ-induced VSMC growth arrest. Mechanistically, p55γ interacted with and stabilized p53 protein by blocking mouse double minute 2 homologue-mediated p53 ubiquitination and degradation, subsequently activating its target gene p21. Concurrently, p55γ up-regulated Bcl-xl expression, resulting in non-apoptotic growth arrest effect. Conclusion These findings mark p55γ as a novel upstream regulator of the p53-p21 signalling pathway that negatively regulatesVSMC proliferation, suggesting that malfunction of p55γ may trigger vascular proliferative disorders.
Bibliographical noteFunding Information:
This work was supported by the National Basic Research Program of China (2012CB944500, 2012CB518000, 2013CB531200), the National Natural Science Foundation of China (9143910034, 81070116, 81370233, 81170100, 81070674, 81130073, 81270190 and 31221002), and the Beijing Municipal Scientific and Technology Commission (2007B005).
© The Author 2014.
- Neointimal formation
- Vascular smooth muscle cell proliferation