DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes
DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes
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DJ-1 通过激活 Nrf2 和随后上调抗氧化酶来介导缺氧预处理的延迟心脏保护。
DOI：
10.1097/fjc.0000000000000257
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发表时间：
2015-08-01
影响因子：
3
通讯作者：
Huang, Qi-Ren
中科院分区：
文献类型：
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作者：
Yan, Yu-Feng;Chen, He-Ping;Huang, Qi-Ren
我们最近发现DJ-1作为一种内源性保护蛋白参与了低氧预适应(HPC)对缺氧/复氧(H/R)损伤的延迟心脏保护作用。本研究旨在进一步探讨DJ-1介导HPC对H/R诱导的氧化应激的延迟心脏保护作用的可能机制。利用大鼠心脏来源的H9c2细胞的HPC细胞模型，我们发现HPC促进核因子红系相关因子2(Nrf2)及其胞浆抑制剂Kelch样ECH相关蛋白-1(Keap1)的解离，并导致HPC后24小时Nrf2的核转位、抗氧化反应元件结合和转录活性增加，随后锰超氧化物歧化酶(MnSOD)和血红素加氧酶-1(HO-1)上调，从而对正常H9c2细胞的H/R诱导的氧化应激提供延迟保护。然而，在DJ-1基因敲除的H9c2细胞中，HPC的上述作用被取消，并通过恢复DJ-1的表达而恢复。重要的是，我们发现抑制H9c2细胞中的Nrf2通路类似于DJ-1基因敲除的效果，并取消了HPC诱导的抗氧化酶(MnSOD和HO-1)和延迟的心脏保护作用。此外，抑制Nrf2还逆转了DJ-1基因敲除的H9c2细胞中恢复表达的DJ-1对抗氧化酶的诱导和HPC延迟的心脏保护作用。综上所述，这项工作揭示了Nrf2途径的激活和随后的抗氧化酶的上调可能是DJ-1介导HPC对H/R诱导的H9c2细胞氧化应激的延迟心脏保护的关键机制。
We have recently shown that DJ-1 is implicated in the delayed cardioprotective effect of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R) injury as an endogenous protective protein. This study aims to further investigate the underlying mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress. Using a well-characterized cellular model of HPC from rat heart-derived H9c2 cells, we found that HPC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein-1 (Keap1) dissociation and resulted in increased nuclear translocation, antioxidant response element-binding, and transcriptional activity of Nrf2 24 hours after HPC, with subsequent upregulation of manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1), which provided delayed protection against H/R-induced oxidative stress in normal H9c2 cells. However, the aforementioned effects of HPC were abolished in DJ-1-knockdown H9c2 cells, which were restored by restoration of DJ-1 expression. Importantly, we showed that inhibition of the Nrf2 pathway in H9c2 cells mimicked the effects of DJ-1 knockdown and abolished HPC-derived induction of antioxidative enzymes (MnSOD and HO-1) and the delayed cardioprotection. In addition, inhibition of Nrf2 also reversed the effects of restored DJ-1 expression on induction of antioxidative enzymes and delayed cardioprotection by HPC in DJ-1-knockdown H9c2 cells. Taken together, this work revealed that activation of Nrf2 pathway and subsequent upregulation of antioxidative enzymes could be a critical mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress in H9c2 cells.