Ma Yuanji, Chen Zhaoyang, Zou Yunzeng, Ge Junbo
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China ; Institute of Biomedical Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Oxid Med Cell Longev. 2014;2014:148798. doi: 10.1155/2014/148798. Epub 2014 Jul 3.
Dendritic cells (DCs), which are highly proficient antigen-presenting cells, play a complex role in both the initiation and progression of atherosclerosis. We tested the hypothesis that the anti-inflammatory and antioxidant effects of atorvastatin may be partly mediated by the phosphatidylinositol 3-kinase/protein kinase B/transcription factor nuclear factor-erythroid 2-related factor 2 (PI3K/Akt/Nrf 2) pathway via the attenuation of DC maturation, thus reducing the inflammatory and oxidative stress responses. This study showed that angiotensin 2 (Ang 2) induced the maturation of DCs, stimulated CD83, CD40, CD80, and CD86 expression, and increased the secretion of IL-12p70, IL-6, and TNF-α. These effects were suppressed by atorvastatin. Atorvastatin also lowered the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), counteracting their initial increases in response to Ang 2 stimulation. Atorvastatin activated Nrf 2 via the PI3K/Akt pathway and thereby promoted Nrf 2 translocation from the cytoplasm to the nucleus in bone marrow-derived dendritic cells (BMDCs), a process that was reversed by the PI3K inhibitor LY294002. Therefore, the regulation of Nrf 2 expression by the PI3K/Akt pathway plays an important role in the regulation of the statin-mediated antioxidant and anti-inflammatory responses in DCs.
树突状细胞（DCs）是高效的抗原呈递细胞，在动脉粥样硬化的起始和进展过程中发挥着复杂的作用。我们检验了这样一个假设：阿托伐他汀的抗炎和抗氧化作用可能部分是通过磷脂酰肌醇3激酶/蛋白激酶B/转录因子核因子红细胞2相关因子2（PI3K/Akt/Nrf 2）途径介导的，该途径通过减弱DC成熟，从而减少炎症和氧化应激反应。本研究表明，血管紧张素2（Ang 2）诱导DC成熟，刺激CD83、CD40、CD80和CD86表达，并增加IL-12p70、IL-6和TNF-α的分泌。这些作用被阿托伐他汀抑制。阿托伐他汀还降低了活性氧（ROS）和丙二醛（MDA）的水平，抵消了它们因Ang 2刺激而最初出现的升高。阿托伐他汀通过PI3K/Akt途径激活Nrf 2，从而促进骨髓来源的树突状细胞（BMDCs）中Nrf 2从细胞质向细胞核的转位，这一过程被PI3K抑制剂LY294002逆转。因此，PI3K/Akt途径对Nrf 2表达的调节在他汀介导的DC抗氧化和抗炎反应调节中起重要作用。
