Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms
Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms
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AMPK激活抑制PDGF诱导的肺动脉平滑肌细胞增殖及其潜在机制
DOI：
10.1016/j.phrs.2016.03.010
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发表时间：
2016-05-01
影响因子：
9.3
通讯作者：
Li, Manxiang
中科院分区：
文献类型：
--
作者：
Song, Yang;Wu, Yuanyuan;Li, Manxiang
本研究的目的是研究PDGF诱导的肺动脉平滑肌细胞（PASMC）增殖的信号转导机制，并确定AMPK激活对PDGF诱导的PASMC增殖的影响及其潜在机制。PDGF激活PI 3 K/Akt/mTOR信号通路，上调Skp 2表达，抑制p27表达，促进PASMC增殖。PASMC与二甲双胍的预先孵育诱导了显著的AMPK活化，并显著阻断了PDGF诱导的细胞增殖。缺乏AMPK α 2的PASMC对二甲双胍对PDGF诱导的细胞增殖的抑制作用具有抗性。二甲双胍不影响Akt激活，但阻断mTOR磷酸化对PDGF的反应;这些都伴随着Skp 2上调和p27减少的逆转。我们的研究表明AMPK的激活负性调节mTOR活性从而抑制PASMC的增殖，因此在通过负性调节肺血管重构来预防和治疗肺动脉高压中具有潜在的价值。(C)2016爱思唯尔有限公司版权所有
The aims of the present study were to examine signaling mechanisms for PDGF-induced pulmonary arterial smooth muscle cells (PASMC) proliferation and to determine the effect of AMPK activation on PDGF-induced PASMC proliferation and its underlying mechanisms. PDGF activated PI3K/Akt/mTOR signaling pathway, and this in turn up-regulated Skp2 and consequently reduced p27 leading to PASMC proliferation. Prior incubation of PASMC with metformin induced a dramatic AMPK activation and significantly blocked PDGF-induced cell proliferation. PASMC lacking AMPK alpha 2 were resistant to the inhibitory effect of metformin on PDGF-induced cell proliferation. Metformin did not affect Akt activation but blocked mTOR phosphorylation in response to PDGF; these were accompanied by the reversion of Skp2 up-regulation and p27 reduction. Our study suggests that the activation of AMPK negatively regulates mTOR activity to suppress PASMC proliferation and therefore has a potential value in the prevention and treatment of pulmonary hypertension by negatively modulating pulmonary vascular remodeling. (C) 2016 Elsevier Ltd. All rights reserved.