SirT1 Regulation of Antioxidant Genes Is Dependent on the Formation of a FoxO3a/PGC-1α Complex
SirT1 Regulation of Antioxidant Genes Is Dependent on the Formation of a FoxO3a/PGC-1α Complex
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DOI：
10.1089/ars.2012.4713
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发表时间：
2013-11-01
影响因子：
6.6
通讯作者：
Monsalve, Maria
中科院分区：
文献类型：
--
作者：
Olmos, Yolanda;Sanchez-Gomez, Francisco J.;Monsalve, Maria
SirT 1是一种III类组蛋白脱乙酰酶，参与代谢和活性氧的控制。在血管系统中，它已被证明可以减少内皮超氧化物的产生，防止内皮功能障碍和动脉粥样硬化。然而，介导SirT 1抗氧化功能的机制仍有待鉴定。转录因子FoxO 3a和转录辅激活因子过氧化物酶体增殖物激活受体-辅激活因子1（PGC-1）已被证明可诱导抗氧化基因的表达，并被SirT 1脱乙酰化。目的：研究SirT 1对抗氧化基因的调控以及FoxO 3a和PGC-1在其中的作用。结果如下：我们发现，SirT 1调节牛主动脉内皮细胞中的几个抗氧化基因的表达，包括锰超氧化物歧化酶（MnSOD），过氧化氢酶，过氧化物酶3和5（Prx 3，Prx 5），硫氧还蛋白2（Trx 2），硫氧还蛋白还原酶2（TR 2），和解偶联蛋白2（UCP-2），并可以定位在这些基因的调控区域。我们还发现，FoxO 3a或PGC-1的敲低阻止了SirT 1过表达诱导抗氧化基因。此外，SirT 1增加了FoxO 3a/PGC-1复合物的形成，通过免疫共沉淀（IP）测定，同时减少H2 O2依赖性FoxO 3a和PGC-1乙酰化。数据显示FoxO 3a敲低增加PGC-1乙酰化水平，反之亦然，表明SirT 1对FoxO 3a和PGC-1的活性可能依赖于FoxO 3a/PGC-1复合物的形成。创新：建议SirT 1活动的统一机制。结论：SirT 1对血管内皮细胞抗氧化基因的调控依赖于FoxO 3a/PGC-1复合物的形成。抗氧化剂。氧化还原信号。19，1507-1521.
SirT1 is a class III histone deacetylase that has been implicated in metabolic and reactive oxygen species control. In the vasculature it has been shown to decrease endothelial superoxide production, prevent endothelial dysfunction and atherosclerosis. However, the mechanisms that mediate SirT1 antioxidant functions remain to be characterized. The transcription factor FoxO3a and the transcriptional coactivator peroxisome proliferator activated receptor -coactivator 1 (PGC-1) have been shown to induce the expression of antioxidant genes and to be deacetylated by SirT1. Aims: Here we investigated SirT1 regulation of antioxidant genes and the roles played by FoxO3a and PGC-1 in this regulation. Results: We found that SirT1 regulates the expression of several antioxidant genes in bovine aortic endothelial cells, including Mn superoxide dismutase (MnSOD), catalase, peroxiredoxins 3 and 5 (Prx3, Prx5), thioredoxin 2 (Trx2), thioredoxin reductase 2 (TR2), and uncoupling protein 2 (UCP-2) and can be localized in the regulatory regions of these genes. We also found that knockdown of either FoxO3a or PGC-1 prevented the induction of antioxidant genes by SirT1 over-expression. Furthermore, SirT1 increased the formation of a FoxO3a/PGC-1 complex as determined by co-immunoprecipitation (IP) assays, concomitantly reducing H2O2-dependent FoxO3a and PGC-1 acetylation. Data showing that FoxO3a knockdown increases PGC-1 acetylation levels and vice versa, suggest that SirT1 activity on FoxO3a and PGC-1 may be dependent of the formation of a FoxO3a/PGC-1 complex. Innovation: A unifying mechanism for SirT1 activities is suggested. Conclusion: We show that SirT1 regulation of antioxidant genes in vascular endothelial cells depends on the formation of a FoxO3a/PGC-1 complex. Antioxid. Redox Signal. 19, 1507-1521.