Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27.
Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27.
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DOI：
10.1097/01.asn.0000129839.91567.68
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发表时间：
2004-07
期刊：
影响因子：
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通讯作者：
L. Zeng;Hanshi Xu;T. Chew;R. Chisholm;M. Sadeghi;Y. Kanwar;Farhad R. Danesh
中科院分区：
文献类型：
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作者：
L. Zeng;Hanshi Xu;T. Chew;R. Chisholm;M. Sadeghi;Y. Kanwar;Farhad R. Danesh
最近的实验观察表明，他汀类药物可能会发挥调节作用，对一些病理生物学过程超出其降胆固醇的属性。他汀类药物的一些多效性作用似乎是通过其阻断类异戊二烯中间体合成的能力介导的，类异戊二烯中间体作为小GTP结合蛋白的适当功能和活化所需的重要脂质附着。本研究探讨了辛伐他汀（SMV）对血管紧张素II（Ang II）诱导的Rac1介导的细胞周期蛋白依赖性激酶抑制剂p27上调的调节作用。Ang II（100 nM）刺激大鼠系膜细胞诱导p27蛋白表达的显着增加。用SMV（1 μ M）共同处理细胞可抑制Ang II诱导的p27蛋白上调。加入甲羟戊酸（200 μ M）或香叶基香叶基焦磷酸（5 μ M）逆转了SMV对p27蛋白表达的抑制作用，表明SMV的作用是香叶基香叶基依赖性的。这项研究还提供了证据，血管紧张素II刺激和下游激活的Rac1，细胞内H2O2的生产，Akt激酶导致的p27蛋白在系膜细胞的上调之间的顺序联系。SMV通过抑制Rac1的活性，逆转了Ang II诱导的细胞内H2O2产生、Akt激活和p27蛋白表达的增加。本研究不仅阐明了系膜细胞中Ang II介导的信号级联反应，而且首次证实了SMV在细胞周期水平上对Ang II诱导的信号通路的调节作用。
Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 microM) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 microM) or geranylgeranyl pyrophosphate (5 microM) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.