Department of Internal Medicine, The Fourth People's Hospital of Chengdu, Chengdu, Sichuan, China.
Department of Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
J Pharmacol Sci. 2021 Jan;145(1):105-114. doi: 10.1016/j.jphs.2020.10.007. Epub 2020 Oct 30.
Brain microvascular endothelial cells (BMECs) dysfunction is related to the pathogenesis of neurovascular complication of diabetes mellitus that adversely lead to various CNS disorders. Mitoquinone (MitoQ) is a mitochondria targeted antioxidant that exerts multiple protective effects in many oxidative damage-related diseases. In this study, we determined the protective effects of MitoQ on high glucose (HG)-induced BMECs injury and investigated the underlying mechanism. We found that HG significantly reduced the expression of Nrf2 and HO-1, decreased mitochondrial membrane potential, increased intracellular and mitochondrial reactive oxygen species (ROS) generation, induced cytoskeletal damage and apoptosis in BMECs. In addition, Mito tempol, a mitochondrial ROS scavenger, significantly reduced HG-induced mitochondrial ROS production and attenuated cytoskeletal damage and cell apoptosis, suggesting MtROS production was involved in HG-induced BMECs injury. Moreover, we found that MitoQ treatment significantly upregulated the expression of Nrf2 and HO-1 in HG-induced BMECs, which is accompanied by improved mitochondrial membrane potential and decreased MtROS production. Meanwhile, MitoQ treatment also remarkably attenuated HG-induced cytoskeletal damage and cell apoptosis in BMECs. However, inhibitor of Nrf2 with ML385 impaired the protective effects of MitoQ in HG-induced BMECs. In conclusion, our results suggest that MitoQ exerts protective effect on HG-induced BMECs injury via activating Nrf2/HO-1 pathway.
脑微血管内皮细胞（BMEC）功能障碍与糖尿病神经血管并发症的发病机制有关，会导致各种中枢神经系统疾病。Mitoquinone（MitoQ）是一种靶向线粒体的抗氧化剂，在许多氧化损伤相关疾病中发挥多种保护作用。在这项研究中，我们确定了 MitoQ 对高葡萄糖（HG）诱导的 BMEC 损伤的保护作用，并研究了其潜在机制。我们发现 HG 显著降低了 Nrf2 和 HO-1 的表达，降低了线粒体膜电位，增加了细胞内和线粒体活性氧（ROS）的产生，诱导了 BMECs 的细胞骨架损伤和细胞凋亡。此外，线粒体 ROS 清除剂 Mito tempol 显著减少了 HG 诱导的线粒体 ROS 产生，并减轻了细胞骨架损伤和细胞凋亡，表明 MtROS 的产生参与了 HG 诱导的 BMECs 损伤。此外，我们发现 MitoQ 处理显著上调了 HG 诱导的 BMECs 中 Nrf2 和 HO-1 的表达，伴随着线粒体膜电位的改善和 MtROS 产生的减少。同时，MitoQ 处理还显著减轻了 HG 诱导的 BMECs 中的细胞骨架损伤和细胞凋亡。然而，Nrf2 的抑制剂 ML385 损害了 MitoQ 在 HG 诱导的 BMECs 中的保护作用。总之，我们的结果表明，MitoQ 通过激活 Nrf2/HO-1 通路对 HG 诱导的 BMECs 损伤发挥保护作用。
