Nakao Takafumi, Shiota Masayuki, Tatemoto Yasuyoshi, Izumi Yasukatsu, Iwao Hiroshi
Department of Pharmacology, Osaka City University Medical School, Asahimachi, Osaka, Japan.
J Pharmacol Sci. 2007 Dec;105(4):334-41. doi: 10.1254/jphs.fp0070682. Epub 2007 Dec 1.
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.
羟甲基戊二酸单酰辅酶A还原酶抑制剂（他汀类药物）已被证明具有多种与胆固醇水平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）增殖和迁移是血管生成的关键事件，已知他汀类药物可增强这些事件。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。在本研究中，我们表明Akt及其下游靶点雷帕霉素哺乳动物靶点（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著增强了大鼠主动脉内皮细胞（rAECs）的增殖和迁移。向rAECs中添加普伐他汀导致Akt和p70 S6激酶（p70S6K）快速磷酸化。磷脂酰肌醇3激酶（PI3K）的特异性抑制剂LY294002阻断了Akt和p70S6K磷酸化，而mTOR的特异性抑制剂雷帕霉素仅抑制普伐他汀诱导的p70S6K磷酸化。此外，LY294002和雷帕霉素均抑制普伐他汀诱导的rAEC增殖和迁移。综上所述，我们的研究结果表明，普伐他汀以这种顺序激活PI3K/Akt/mTOR /p70S6K信号通路，并且该通路有助于普伐他汀诱导的rAEC增殖和迁移。
