Identification of PI3K regulatory subunit p55γ as a novel inhibitor of vascular smoothmuscle cell proliferation and neointimal formation

Geng Li, Ning Xie, Yuan Yao, Yan Zhang, Jiaojiao Guo, Yuanqing Feng, Fengxiang Lv, Rui Ping Xiao, Chun Mei Cao

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17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)75-85
Number of pages11
JournalCardiovascular Research
Issue number1
StatePublished - Jan 1 2015

Bibliographical note

Publisher Copyright:
© The Author 2014.


  • Neointimal formation
  • P55γ
  • Restenosis
  • Vascular smooth muscle cell proliferation


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