Habeos Ioannis G, Ziros Panos G, Chartoumpekis Dionysios, Psyrogiannis Agathoklis, Kyriazopoulou Venetsana, Papavassiliou Athanasios G
Department of Internal Medicine, School of Medicine, University of Patras, 26500, Patras, Greece.
J Mol Med (Berl). 2008 Nov;86(11):1279-85. doi: 10.1007/s00109-008-0393-4. Epub 2008 Sep 2.
Some of the statins' pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress.
一些他汀类药物的多效性作用归因于其抗氧化活性。Nrf2转录因子可控制许多保护性基因在氧化应激反应中的表达。在本研究中，采用Wistar大鼠、原代肝细胞以及ST2细胞，以探究Nrf2在介导他汀类药物所报道的抗氧化作用中的潜在作用。辛伐他汀以甲羟戊酸依赖性和胆固醇非依赖性方式触发大鼠肝脏和原代大鼠肝细胞中Nrf2的核转位。在肝脏中，辛伐他汀处理的大鼠的核提取物中，Nrf2的DNA结合活性显著增加，并且诱导了Nrf2的两个已知靶标（HO-1和GPX2）的mRNA表达。在稳定转染了带有Nrf2结合位点（抗氧化反应元件）构建体的ST2细胞中，辛伐他汀以甲羟戊酸依赖性和胆固醇非依赖性方式增强了Nrf2介导的转录活性。总之，辛伐他汀激活Keap1/Nrf2信号通路可能为细胞提供有效的保护，使其免受氧化应激的有害影响。
