Cortese Miriam M, Suschek Christoph V, Wetzel Wiebke, Kröncke Klaus-D, Kolb-Bachofen Victoria
Institute of Molecular Medicine, Research Group Immunobiology, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Free Radic Biol Med. 2008 Jun 15;44(12):2002-12. doi: 10.1016/j.freeradbiomed.2008.02.013. Epub 2008 Mar 8.
Oxidative stress is one of the main causes of vascular disease. This study aims to investigate the antioxidant activity exerted by zinc in primary rat endothelial cells (EC). Using a 24-h treatment with hydrogen peroxide as a model for oxidative stress, we found that zinc supplementation protects from peroxide-induced cell death via increasing the transcription of the catalytic subunit (heavy chain) of glutamate-cysteine ligase (GCLC) and the concentrations of glutathione (GSH). Conversely, zinc depletion significantly decreased the expression of GCLC and the cellular GSH levels, resulting in an increased susceptibility of EC to oxidative stress. Using confocal microscopy and the RNA silencing technique, we found that zinc upregulates the expression of GCLC by activating the transcription factor Nrf2. Surprisingly, the intracellular zinc sensor, metal-responsive transcription factor-1, is not involved in the zinc-induced expression of GCLC. The present study shows that zinc controls the redox state of EC by regulating the de novo synthesis of GSH. This molecular mechanism may contribute to the elaboration of new nutritional and/or pharmaceutical approaches for protecting the endothelium against oxidative stress.
氧化应激是血管疾病的主要原因之一。本研究旨在调查锌在原代大鼠内皮细胞（EC）中发挥的抗氧化活性。以用过氧化氢进行24小时处理作为氧化应激模型，我们发现补充锌可通过增加谷氨酸-半胱氨酸连接酶（GCLC）催化亚基（重链）的转录和谷胱甘肽（GSH）的浓度来保护细胞免受过氧化物诱导的细胞死亡。相反，锌缺乏显著降低了GCLC的表达和细胞内GSH水平，导致内皮细胞对氧化应激的易感性增加。使用共聚焦显微镜和RNA沉默技术，我们发现锌通过激活转录因子Nrf2上调GCLC的表达。令人惊讶的是，细胞内锌传感器金属反应性转录因子-1不参与锌诱导的GCLC表达。本研究表明，锌通过调节GSH的从头合成来控制内皮细胞的氧化还原状态。这种分子机制可能有助于开发新的营养和/或药物方法来保护内皮细胞免受氧化应激。
