Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis
Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis
复制标题
丹参酮 IIA 通过调节氧化还原稳态和谷氨酰胺分解激活核因子红细胞 2 相关因子 2 抑制肺纤维化
DOI：
10.1089/ars.2018.7569
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发表时间：
2018-09-22
影响因子：
6.6
通讯作者：
Chen, Jun
中科院分区：
文献类型：
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作者：
An, Lin;Peng, Li-Ying;Chen, Jun
目的：肺纤维化（PF）以氧化应激激活肌成纤维细胞为特征。然而，肌成纤维细胞转分化的精确调控在很大程度上仍未被描述。结果：本研究发现丹参酮IIA （tanshinone IIA, Tan-IIA）是丹参根中的一种活性成分，可通过调控核因子-红细胞2相关因子2 (Nrf2)，抑制博来霉素（BLM）应激小鼠活性氧（ROS）介导的肌成纤维细胞活化，减少细胞外基质沉积。此外，Tan-IIA通过抑制NADPH氧化酶4上调Nrf2来恢复氧化还原稳态，并通过阻断ros介导的蛋白激酶C δ (PKC δ)/Smad3信号传导有效地阻止肌成纤维细胞活化。在blm处理的小鼠的成纤维细胞和肺中，Nrf2的敲低降低了Tan-IIA的抑制作用，表明Nrf2在Tan-IIA活性中的重要作用。Tan-IIA通过促进Keap1的降解来破坏kelch-like ECH-associated protein 1 （Keap1）与Nrf2的结合，从而通过保护Nrf2抗泛素化和蛋白酶体降解的稳定性来增加Nrf2的诱导。重要的是，我们还发现谷氨酸回调通路参与了激活的肌成纤维细胞的能量生成和生物合成及其增殖。Tan-IIA通过激活Nrf2将谷氨酰胺水解转化为谷胱甘肽（GSH）产生，导致谷氨酸在三羧酸循环中的可用性降低。最终，肌成纤维细胞的激活通过损害细胞增殖而被阻止。创新与结论：除了调节氧化还原稳态外，我们的研究表明，Tan-IIA激活Nrf2/GSH信号通路，限制肌成纤维细胞增殖中的谷氨酰胺水解，这为Nrf2在PF中的关键功能提供了进一步的见解。
Aims: Pulmonary fibrosis (PF) is characterized by myofibroblast activation through oxidative stress. However, the precise regulation of myofibroblast transdifferentiation remains largely uncharacterized.Results: In this study, we found that tanshinone IIA (Tan-IIA), an active component in the root of Salvia miltiorrhiza Bunge, can suppress reactive oxygen species (ROS)-mediated activation of myofibroblast and reduce extracellular matrix deposition in bleomycin (BLM)-challenged mice through the regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). Additionally, Tan-IIA restored redox homeostasis by upregulating Nrf2 with NADPH oxidase 4 suppression and effectively prevented myofibroblast activation by blocking ROS-mediated protein kinase C delta (PKC delta)/Smad3 signaling. Nrf2 knockdown in the fibroblasts and the lungs of BLM-treated mice reduced the inhibitory effects of Tan-IIA, indicating the essential role of Nrf2 in the Tan-IIA activity. Tan-IIA impaired the binding of kelch-like ECH-associated protein 1 (Keap1) to Nrf2 by promoting the degradation of Keap1 and thereby increasing Nrf2 induction by protecting Nrf2 stability against ubiquitination and proteasomal degradation. Importantly, we also found that the glutamate anaplerotic pathway was involved in energy generation and biosynthesis in activated myofibroblasts and their proliferation. Tan-IIA shunted glutaminolysis into glutathione (GSH) production by activating Nrf2, resulting in the reduction of glutamate availability for tricarboxylic acid cycle. Ultimately, myofibroblast activation was prevented by impairing cell proliferation.Innovation and Conclusion: In addition to the regulation of redox homeostasis, our work showed that Tan-IIA activated Nrf2/GSH signaling pathway to limit glutaminolysis in myofibroblast proliferation, which provided further insight into the critical function of Nrf2 in PF.