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Downregulation of FOXO6 alleviates hypoxia-induced apoptosis and oxidative stress in cardiomyocytes by enhancing Nrf2 activation via upregulation of SIRT6
Journal of Bioenergetics and Biomembranes ( IF 3 ) Pub Date : 2020-10-29 , DOI: 10.1007/s10863-020-09856-2
Aiping Jin 1 , Qianrong Zhang 1 , Shulin Li 1 , Bing Li 1
Affiliation  

Forkhead box protein O6 (FOXO6) has been recently identified as a novel regulator of oxidative stress in multiple pathological processes. However, whether FOXO6 participates in the regulation of oxidative stress of myocardial infarction is unclear. The present study was performed to evaluate the potential role of FOXO6 in regulating hypoxia-induced apoptosis and oxidative stress in cardiomyocytes in vitro. Our results demonstrated that FOXO6 expression was highly elevated in cardiomyocytes exposed to hypoxia. Downregulation of FOXO6 expression by the siRNA-mediated gene knockdown in hypoxia-exposed cardiomyocytes increased cell viability, while repressing apoptosis and reactive oxygen species (ROS) production. In contrast, overexpression of FOXO6 enhanced the sensitivity of cardiomyocytes to hypoxia-induced injury. Further, in-depth research revealed that knockdown of FOXO6 promoted the expression of sirtuin6 (SIRT6) and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling. Moreover, SIRT6 inhibition markedly blocked the FOXO6 knockdown-induced promotion effect on Nrf2 activation. In addition, Nrf2 inhibition partially reversed the FOXO6 knockdown-mediated protective effect against hypoxia-induced cardiomyocyte injury. Taken together, the findings of our study demonstrate that knockdown of FOXO6 is capable of protecting cardiomyocytes from hypoxia-induced apoptosis and oxidative stress by enhancing Nrf2 activation via upregulation of SIRT6. Our study highlights a potential role of FOXO6 in myocardial infarction and suggests it as an attractive target for cardioprotection.



中文翻译:

下调 FOXO6 通过上调 SIRT6 增强 Nrf2 活化来减轻缺氧诱导的心肌细胞凋亡和氧化应激

叉头盒蛋白 O6 (FOXO6) 最近被确定为多种病理过程中氧化应激的新型调节剂。然而,FOXO6是否参与心肌梗死氧化应激的调节尚不清楚。本研究旨在评估 FOXO6 在体外调节缺氧诱导的心肌细胞凋亡和氧化应激中的潜在作用。我们的结果表明,FOXO6 表达在暴露于缺氧的心肌细胞中高度升高。在缺氧暴露的心肌细胞中,通过 siRNA 介导的基因敲低下调 FOXO6 表达增加了细胞活力,同时抑制了细胞凋亡和活性氧 (ROS) 的产生。相反,FOXO6 的过表达增强了心肌细胞对缺氧诱导的损伤的敏感性。更远,深入研究表明,敲除 FOXO6 可促进 Sirtuin6 (SIRT6) 的表达,并增强核因子红细胞 2 相关因子 2 (Nrf2) 介导的抗氧化信号的激活。此外,SIRT6 抑制显着阻断了 FOXO6 敲低诱导的 Nrf2 激活促进作用。此外,Nrf2 抑制部分逆转了 FOXO6 敲低介导的对缺氧诱导的心肌细胞损伤的保护作用。总之,我们的研究结果表明,FOXO6 的敲低能够通过上调 SIRT6 增强 Nrf2 活化来保护心肌细胞免受缺氧诱导的细胞凋亡和氧化应激。我们的研究强调了 FOXO6 在心肌梗死中的潜在作用,并表明它是一个有吸引力的心脏保护目标。

更新日期:2020-10-30
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