Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3
Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3
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DOI：
10.1074/jbc.m710098200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Littlewood, Trevor D.
中科院分区：
文献类型：
--
作者：
Allard, David;Figg, Nichola;Littlewood, Trevor D.
血管平滑肌细胞（VSMCs）凋亡可导致动脉粥样硬化斑块不稳定和破裂，导致心肌梗死、中风和猝死。然而，介导动脉粥样硬化斑块中VSMCs存活的分子机制仍不清楚。尽管与正常VSMC相比，斑块VSMC表现出对凋亡的敏感性增加和IGF 1受体（IGF 1 R）表达减少，但尚未确定其致病作用。在这里，我们表明IGF 1 R表达的增加可以拯救斑块VSMC免受氧化应激诱导的细胞凋亡，这表明IGF-1信号传导是VSMC生存的关键调节因子。Akt介导大部分IGF 1 R存活信号传导，并且Akt的异位激活足以在体外保护VSMC。IGF 1 R和磷酸化Akt的表达在人斑块（内膜）VSMCs中与中膜VSMCs相比均降低，表明Akt介导动脉粥样硬化中的存活信号。重要的是，Akt的下游靶点被鉴定为介导其保护作用，如通过Akt依赖性磷酸化抑制FoxO 3a或GSK 3在体外保护VSMC。我们的结论是Akt及其下游靶点FoxO 3a和GSK 3调节VSMCs的生存途径，并且由于IGF 1 R信号转导的减少，它们的失调可能促进动脉粥样硬化中的细胞凋亡。
Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.