Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection
Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection
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DOI：
10.1007/s11010-013-1812-6
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发表时间：
2014-01-01
影响因子：
4.3
通讯作者：
Huang, Qi-Ren
中科院分区：
文献类型：
--
作者：
Huang, Xiao-Shan;Chen, He-Ping;Huang, Qi-Ren
低氧预处理（HPC）可通过上调血红素氧合酶-1（HO-1）、锰超氧化物歧化酶（MnSOD）等多种抗氧化酶的表达，减轻缺氧/复氧（H/R）引起的氧化应激，发挥延迟性心肌保护作用，但其机制尚不清楚。核因子红细胞2相关因子2（Nrf 2）是一种重要的转录因子，通过与抗氧化反应元件（ARE）结合来调节几种抗氧化基因的表达，并在细胞防御氧化应激中起着至关重要的作用。在这里，我们想知道Nrf 2-ARE通路的激活是否是HPC诱导抗氧化酶的原因，并有助于HPC的延迟心脏保护。在H/R前24 h诱导来自大鼠心脏来源的H9 c2细胞的HPC细胞模型。结果表明，HPC有效地减轻了H/R诱导的细胞活力丧失和乳酸脱氢酶渗漏。此外，HPC还能促进细胞核转位和晚期Nrf 2的ARE结合，上调抗氧化酶HO-1和MnSOD的表达，抑制H/R诱导的氧化应激。然而，当用siRNA特异性敲低Nrf 2时，HPC对抗氧化酶的诱导被完全取消，因此，HPC对H/R诱导的氧化应激的抑制作用被逆转，HPC诱导的延迟性心脏保护也被取消。这些结果表明，HPC通过激活Nrf 2-ARE途径上调抗氧化酶，并赋予延迟心脏保护作用，以对抗H/R诱导的氧化应激。
It has been well demonstrated that hypoxic preconditioning (HPC) can attenuate hypoxia/reoxygenation (H/R)-induced oxidant stress and elicit delayed cardioprotection by upregulating the expression of multiple antioxidative enzymes such as heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and so on. However, the underlying mechanisms of HPC-induced upregulation of antioxidative enzymes are not fully understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element (ARE) and plays a crucial role in cellular defence against oxidative stress. Here, we wondered whether activation of the Nrf2-ARE pathway is responsible for the induction of antioxidative enzymes by HPC and contributes to the delayed cardioprotection of HPC. Cellular model of HPC from rat heart-derived H9c2 cells was induced 24 h prior to H/R. The results showed that HPC efficiently attenuated H/R-induced viability loss and lactate dehydrogenase leakage. In addition, HPC increased nuclear translocation and ARE binding of Nrf2 during the late phase, upregulated the expression of antioxidative enzymes (HO-1 and MnSOD), inhibited H/R-induced oxidant stress. However, when Nrf2 was specifically knocked down by siRNA, the induction of antioxidative enzymes by HPC was completely abolished and, as a result, the inhibitory effect of HPC on H/R-induced oxidant stress was reversed, and the delayed cardioprotection induced by HPC was also abolished. These results suggest that HPC upregulates antioxidative enzymes through activating the Nrf2-ARE pathway and confers delayed cardioprotection against H/R-induced oxidative stress.