Overexpression of FGF19 alleviates hypoxia/reoxygenation-induced injury of cardiomyocytes by regulating GSK-3β/Nrf2/ARE signaling
Overexpression of FGF19 alleviates hypoxia/reoxygenation-induced injury of cardiomyocytes by regulating GSK-3β/Nrf2/ARE signaling
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DOI：
10.1016/j.bbrc.2018.06.161
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发表时间：
2018-09-18
影响因子：
3.1
通讯作者：
Yuan, Zuyi
中科院分区：
文献类型：
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作者：
Fang, Yuan;Zhao, Yan;Yuan, Zuyi
成纤维细胞生长因子19（FGF 19）已成为一个重要的细胞保护调节剂，拮抗细胞凋亡和氧化应激在不利条件下。然而，FGF 19是否在心肌缺血/再灌注损伤中发挥细胞保护作用仍不清楚。本研究旨在探讨FGF 19在缺氧/复氧（H/R）诱导的心肌细胞损伤中的作用。我们发现，FGF 19的表达上调响应H/R处理的心肌细胞。FGF 19的沉默显著抑制了H/R处理的心肌细胞的活力，并增加了细胞凋亡和活性氧（ROS）的产生。相反，FGF 19的过表达提高了存活率，抑制了Hilt处理诱导的细胞凋亡和ROS产生，显示了心脏保护作用。此外，我们发现FGF 19调节糖原合成酶激酶-3 β（GSK-3 β）的磷酸化和核因子E2相关因子2（Nrf 2）的核转位。此外，FGF 19促进Nrf 2介导的抗氧化反应元件（ARE）抗氧化信号传导的活化。值得注意的是，用GSK-3 β抑制剂治疗显著消除了FGF 19沉默对H/R诱导的损伤的不利影响，而Nrf 2的沉默部分阻断了FGF 19介导的针对心肌细胞中H/R诱导的损伤的心脏保护作用。综上所述，我们的研究结果表明，FGF 19通过抑制GSK-3 β活性和促进Nrf 2/ARE信号通路的激活来减轻H/R诱导的心肌细胞凋亡和氧化应激，为预防心肌损伤提供了潜在的治疗靶点。(C)2018爱思唯尔公司All rights reserved.
Fibroblast growth factor 19 (FGF19) has emerged as a crucial cytoprotective regulator that antagonizes cell apoptosis and oxidative stress under adverse conditions. However, whether FGF19 plays a cytoprotective role in preventing myocardial damage during myocardial ischemia/reperfusion injury remains unknown. In this study, we aimed to investigate the potential role of FGF19 in regulating hypoxia/reoxygenation (H/R)-induced injury of cardiomyocytes in vitro. We found that FGF19 expression was upregulated in response to H/R treatment in cardiomyocytes. Silencing of FGF19 significantly inhibited viability and increased apoptosis and reactive oxygen species (ROS) generation in cardiomyocytes with H/R treatment. In contrast, overexpression of FGF19 improved viability and inhibited apoptosis and ROS generation induced by Hilt treatment, showing a cardioprotective effect. Moreover, we found that FGF19 regulated the phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) and the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2). In addition, FGF19 promoted the activation of Nrf2-mediated antioxidant response element (ARE) antioxidant signaling. Notably, treatment with a GSK-3 beta inhibitor significantly abrogated the adverse effects of FGF19 silencing on H/R-induced injury, whereas silencing of Nrf2 partially blocked the FGF19-mediated cardioprotective effect against H/R-induced injury in cardiomyocytes. Taken together, our findings demonstrate that FGF19 alleviates H/R-induced apoptosis and oxidative stress in cardiomyocytes by inhibiting GSK-3 beta activity and promoting the activation of Nrf2/ARE signaling, providing a potential therapeutic target for prevention of myocardial injury. (C) 2018 Elsevier Inc. All rights reserved.