Department of Neurosurgery, Baoji Municipal Central Hospital, Baoji City, 721008, China.
Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, No. 168, Li Tang Road, Changping District, Beijing 102218, China.
Biochem Biophys Res Commun. 2019 Feb 12;509(3):713-721. doi: 10.1016/j.bbrc.2018.12.170. Epub 2019 Jan 9.
Ischemic stroke is the second most common cause of death, a major cause of acquired disability in adults. However, the pathogenesis that contributes to ischemic stroke has not been fully understood. Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase, playing important role in regulating various cellular processes, including oxidative stress and inflammation. However, its effects on cerebral ischemia/reperfusion (IR) are unclear. In the study, we found that DUSP14 expression was decreased responding to IR surgery. Over-expressing DUSP14 reduced the infarction volume of cerebral IR mice. Cognitive dysfunction was also improved in mice with DUSP14 over-expression. Promoting DUSP14 expression markedly reduced the activation of glial cells, as evidenced by the decreases in GFAP and Iba-1 expressions in mice with cerebral IR injury. In addition, inflammatory response induced by cerebral IR injury was inhibited in DUSP14 over-expressed mice, as proved by the reduced expression of tumor necrosis factor (TNF)-α and interleukin 1β (IL-1β). Furthermore, oxidative stress was markedly reduced by DUSP14 over-expression through elevating nuclear factor-erythroid 2 related factor 2 (Nrf-2) signaling pathway. Importantly, we found that DUSP14 could interact with Nrf-1, which thereby protected mice against cerebral IR injury. In vitro, we also found that repressing Nrf-2 expression abrogated DUSP14 over-expression-reduced inflammation and ROS generation. Consistent with the anti-inflammatory effect of DUSP14, reducing the production of reactive oxygen species (ROS) also down-regulated TNF-α and IL-1β expressions. Collectively, elevated DUSP14 alleviated brain damage from cerebral IR injury through Nrf-2-regulated anti-oxidant signaling pathway, and the restraining of inflammatory response. These results suggested that DUSP14 might be a potential therapeutic target to prevent ischemic stroke.
缺血性中风是第二大常见死因，也是成年人获得性残疾的主要原因。然而，导致缺血性中风的发病机制尚未完全阐明。双特异性磷酸酶 14（DUSP14，也称为 MKP6）是一种 MAP 激酶磷酸酶，在调节各种细胞过程中发挥重要作用，包括氧化应激和炎症。然而，其对脑缺血/再灌注（IR）的影响尚不清楚。在研究中，我们发现 DUSP14 的表达在对 IR 手术的反应中降低。过表达 DUSP14 减少了脑 IR 小鼠的梗死体积。DUSP14 过表达的小鼠认知功能也得到改善。促进 DUSP14 表达可显著减少星形胶质细胞的激活，这可通过减少脑 IR 损伤小鼠中 GFAP 和 Iba-1 的表达来证明。此外，在 DUSP14 过表达的小鼠中，脑 IR 损伤诱导的炎症反应受到抑制，如 TNF-α 和 IL-1β 的表达减少所证明的那样。此外，DUSP14 过表达通过上调核因子-红细胞 2 相关因子 2（Nrf-2）信号通路显著减轻氧化应激。重要的是，我们发现 DUSP14 可以与 Nrf-1 相互作用，从而保护小鼠免受脑 IR 损伤。在体外，我们还发现抑制 Nrf-2 表达可消除 DUSP14 过表达减少的炎症和 ROS 生成。与 DUSP14 的抗炎作用一致，减少活性氧（ROS）的产生也下调了 TNF-α 和 IL-1β 的表达。总之，DUSP14 通过 Nrf-2 调节的抗氧化信号通路和炎症反应的抑制减轻脑 IR 损伤引起的脑损伤。这些结果表明，DUSP14 可能是预防缺血性中风的潜在治疗靶点。
