Identification of PI3K regulatory subunit p55γ as a novel inhibitor of vascular smooth muscle cell proliferation and neointimal formation
Identification of PI3K regulatory subunit p55γ as a novel inhibitor of vascular smooth muscle cell proliferation and neointimal formation
复制标题
鉴定 PI3K 调节亚基 p55 γ 作为血管平滑肌细胞增殖和新内膜形成的新型抑制剂
DOI：
10.1093/cvr/cvu235
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发表时间：
2015-01-01
影响因子：
10.8
通讯作者：
Cao, Chun-Mei
中科院分区：
文献类型：
--
作者：
Li, Geng;Xie, Ning;Cao, Chun-Mei
目的和结果磷脂酰肌醇3激酶（PI 3 Ks）在血管生理和病理生理中起关键作用。我们的目的是调查的作用p55 γ，PI 3 Ks的调节亚基，在血管平滑肌细胞（VSMC）增殖和新生内膜形成。方法和结果我们确定p55 γ作为一个重要的因素，抑制VSMC增殖和损伤诱发的新生内膜形成。Western blot和mRNA分析表明，p55 γ表达下降，在球囊损伤的大鼠颈动脉和响应于PDGF-BB和血清治疗培养的VSMCs。p55 γ的过表达抑制，而p55 γ的短发夹RNA敲低促进PDGF-BB和血清诱导的VSMC增殖。重要的是，在体内腺病毒基因转移p55 γ到颈动脉衰减，而敲低p55 γ增强球囊损伤诱导的新生内膜形成。此外，p55 γ依次上调p53和p21，导致细胞周期停滞在S期;小干扰RNA敲低p53或p21阻断p55 γ诱导的VSMC生长停滞。从机制上讲，p55 γ通过阻断小鼠双微体2同源物介导的p53泛素化和降解，随后激活其靶基因p21，与p53蛋白相互作用并稳定p53蛋白。同时，p55 γ上调Bcl-xl的表达，导致非凋亡的growth arrest effect.Conclusion这些发现标志着p55 γ作为一种新的上游调节p53-p21信号通路，负调控VSMC增殖，这表明，p55 γ的功能障碍可能会引发血管增生性疾病。
Aims and results Phosphatidylinositol 3 kinases (PI3Ks) play a pivotal role in vascular physiology and pathophysiology. We aimed to investigate the role of p55 gamma, a regulatory subunit of PI3Ks, in vascular smooth muscle cell (VSMC) proliferation and neointimal formation.Methods and results We identified p55 gamma as an important factor that suppresses VSMC proliferation and injury-evoked neointimal formation. Western blot and mRNA analyses showed that p55 gamma expression declined in balloon-injured rat carotid arteries and in response to PDGF-BB and serum treatment in cultured VSMCs. Overexpression of p55 gamma inhibited, whereas short hairpin RNA knockdown of p55 gamma promoted PDGF-BB- and serum-induced VSMC proliferation. Importantly, in vivo adenoviral gene transfer of p55 gamma into carotid arteries attenuated, while knockdown of p55 gamma enhanced balloon injury-induced neointimal formation. Furthermore, p55 gamma sequentially up-regulated p53 and p21, resulting in cell-cycle arrest in S phase; small-interfering RNA knockdown of either p53 or p21 blocked p55 gamma-induced VSMC growth arrest. Mechanistically, p55 gamma 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, p55 gamma up-regulated Bcl-xl expression, resulting in non-apoptotic growth arrest effect.Conclusion These findings mark p55 gamma as a novel upstream regulator of the p53-p21 signalling pathway that negatively regulates VSMC proliferation, suggesting that malfunction of p55 gamma may trigger vascular proliferative disorders.