School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.
Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China.
J Invest Dermatol. 2017 Oct;137(10):2059-2068. doi: 10.1016/j.jid.2017.05.019. Epub 2017 Jun 6.
Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.
辐射诱导的皮肤损伤是放射治疗的常见副作用，并可能限制放射治疗的持续时间和剂量。大多数早期的工作都集中在消除辐射后活性氧（ROS）；然而，对于 ROS 放大和随后的辐射导致皮肤损伤的机制知之甚少。5、6、7、8-四氢生物蝶呤（BH4）是所有一氧化氮合酶的必需辅助因子。BH4 供应不足会导致一氧化氮合酶解偶联和产生高度氧化的自由基。在这项研究中，我们证明了辐射会破坏 BH4，导致一氧化氮合酶解偶联并增强辐射诱导的 ROS。GTP 环化水解酶 I（GCH1）的过表达，即 BH4 合成的限速酶，可恢复细胞内 BH4 水平和一氧化氮的产生，并减少辐射诱导的 ROS。GCH1 还可保护皮肤细胞和大鼠皮肤免受辐射损伤。我们发现 GCH1 受 NF-E2 相关因子 2 调节，NF-E2 相关因子 2 是细胞抗氧化反应的关键介质。重要的是，我们发现 GCH1 是 NF-E2 相关因子 2 抑制 ROS 产生介导的辐射诱导皮肤损伤的关键效应因子。总之，这项研究的结果说明了 NF-E2 相关因子 2/GCH1/BH4 轴在辐射诱导的皮肤损伤中的关键作用。
