Pravastatin induces rat aortic endothelial cell proliferation and migration via activation of PI3K/Akt/mTOR/p70 S6 kinase signaling
Pravastatin induces rat aortic endothelial cell proliferation and migration via activation of PI3K/Akt/mTOR/p70 S6 kinase signaling
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DOI：
10.1254/jphs.fp0070682
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Iwao, Hiroshi
中科院分区：
文献类型：
--
作者：
Nakao, Takafumi;Shiota, Masayuki;Iwao, Hiroshi
HMG-CoA还原酶抑制剂（他汀类药物）已被证明具有几种与胆固醇谱变化无关的血管保护作用，他汀类药物的这些作用部分是由血管生成的激活引起的。内皮细胞（EC）的增殖和迁移是血管生成的关键事件，他汀类药物是已知的增强这些事件。然而，他汀类药物促进EC增殖和迁移的分子机制尚未完全了解。在这项研究中，我们发现Akt及其下游靶哺乳动物雷帕霉素靶蛋白（mTOR）在普伐他汀诱导的EC增殖和迁移中起重要作用。我们发现，普伐他汀显着增强大鼠主动脉内皮细胞（rAECs）的增殖和迁移。在rAEC中加入普伐他汀导致Akt和p70 S6激酶（p70 S6 K）的快速磷酸化。磷脂酰肌醇3-激酶（PI 3 K）特异性抑制剂LY 294002可阻断Akt和p70 S6 K磷酸化，而mTOR特异性抑制剂雷帕霉素仅抑制普伐他汀诱导的p70 S6 K磷酸化。此外，LY 294002和雷帕霉素均抑制普伐他汀诱导的rAEC增殖和迁移。总之，我们的研究结果表明，普伐他汀激活PI 3 K/Akt/mTOR /p70 S6 K信号以这种顺序的方式，这一途径有助于普伐他汀诱导的rAEC增殖和迁移。
The HMG-CoA reductase inhibitors (statins) have been shown to exert several vascular protective effects that are not related to changes in cholesterol profile, and these effects of statins are partly caused by the activation of angiogenesis. Endothelial cell (EC) proliferation and migration are crucial events for angiogenesis and statins are known to enhance these events. However, the molecular mechanism by which statins promote EC proliferation and migration is not fully understood. In this study, we show Akt and its downstream target mammalian target of rapamycin (mTOR) play an important role in pravastatin-induced EC proliferation and migration. We found that pravastatin significantly enhanced the proliferation and migration of rat aortic endothelial cells (rAECs). The addition of pravastatin to rAECs resulted in rapid phosphorylation of Akt and p70 S6 kinase (p70S6K). LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked both Akt and p70S6K phosphorylation, whereas rapamycin, a specific inhibitor of mTOR, suppressed only p70S6K phosphorylation induced by pravastatin. Furthermore, both LY294002 and rapamycin inhibited pravastatin-induced rAEC proliferation and migration. Taken together, our findings indicate that pravastatin activates PI3K/Akt/mTOR /p70S6K signaling in this sequential manner and this pathway contributes to pravastatin-induced rAEC proliferation and migration.