Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression
Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression
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DOI：
10.1161/01.res.0000185823.73556.06
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发表时间：
2005-10-14
影响因子：
20.1
通讯作者：
Araki, E
中科院分区：
文献类型：
--
作者：
Igata, M;Motoshima, H;Araki, E
血管平滑肌细胞（VSMC）增殖是血管疾病（包括动脉粥样硬化）发生和发展的关键事件。我们研究了腺苷一磷酸激活蛋白激酶（AMPK）的激活是否可以抑制VSMC增殖和抑制细胞周期进程。用AMPK激活剂5-氨基咪唑-4-甲酰胺核糖核苷（AICAR）处理人主动脉平滑肌细胞（HASMCs）或分离的兔动脉，诱导AMPK和乙酰辅酶A羧化酶的磷酸化。AICAR可显著抑制血小板源性生长因子-BB（PDGF-BB）和胎牛血清（FCS）诱导的HASMC增殖。AICAR处理抑制由PDGF-BB或FCS诱导的视网膜母细胞瘤基因产物（Rb）的磷酸化，并增加细胞周期蛋白依赖性激酶抑制剂p21（CIP）的表达，但不增加p27（KIP）的表达。AMPK的药理学抑制或显性负性AMPK的过表达抑制AICAR对细胞增殖和Rb磷酸化的抑制作用，表明AICAR的作用是通过AMPK的激活介导的。细胞周期分析显示AICAR明显增加HASMCs的G 0/G1期细胞数，减少S期和G2/M期细胞数，提示AICAR可诱导细胞周期阻滞。AICAR使HASMCs中p53蛋白和Ser-15磷酸化的p53蛋白表达增加，而AMPK的抑制可阻断AICAR的作用。在离体兔髂动脉中，AICAR还增加FCS诱导的Ser-15磷酸化和p53蛋白表达，并抑制Rb磷酸化。这些数据首次表明AMPK通过p53上调的细胞周期调节抑制VSMC增殖。因此，VSMCs中AMPK的激活可能是预防血管疾病的治疗靶点。
Vascular smooth muscle cell ( VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase ( AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells ( HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside ( AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB ( PDGF-BB) and fetal calf serum ( FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product ( Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21(CIP) but not that of p27(KIP). Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.