Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal
Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal
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DOI：
10.1016/j.redox.2014.04.009
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发表时间：
2014-01-01
期刊：
影响因子：
11.4
通讯作者：
Tochtrop, Gregory P.
中科院分区：
文献类型：
--
作者：
Gatbonton-Schwager, Tonibelle N.;Sadhukhan, Sushabhan;Tochtrop, Gregory P.
4-羟基-2-壬烯醛（4-Hydroxy-2-（E）-nonenal，4-HNE）是氧化应激过程中形成的主要脂质过氧化产物之一。在高浓度下，4-HNE具有细胞毒性，并产生通常与氧化应激驱动疾病的病理学相关的有害作用。或者，在低浓度下，它作为一种信号分子，可以激活保护途径，包括抗氧化剂Nrf 2-Keap 1途径。虽然这些双相信号传导特性已经在许多疾病和途径中被列举，但4-HNE是否具有调节氧化应激驱动的脂质过氧化的能力还有待解决。在这里，我们报告了4-HNE通过调节生物氧化剂一氧化氮（NO）的自动调节机制。利用LPS激活的巨噬细胞诱导生物氧化剂的产生，我们证明，4-HNE调节NO水平通过抑制iNOS的表达。我们说明了一个拟议的模型控制NO的形成，从而在低浓度的4-HNE的负反馈回路保持一个恒定的水平，NO的生产与观察到的拐点在约1 μ M，而在较高的4-HNE浓度正反馈观察。此外，我们证明了NO产生控制的负反馈回路依赖于Nrf 2-Keap 1信号通路。两者合计，4-HNE对NO产生的仔细调节主张这种脂质过氧化产物在正常生理学中的更基本的作用。(C)2014作者由爱思唯尔公司出版
4-Hydroxy-2-(E)-nonenal (4-HNE) is one of the major lipid peroxidation product formed during oxidative stress. At high concentrations, 4-HNE is cytotoxic and exerts deleterious effects that are often associated with the pathology of oxidative stress-driven disease. Alternatively, at low concentrations it functions as a signaling molecule that can activate protective pathways including the antioxidant Nrf2-Keap1 pathway. Although these biphasic signaling properties have been enumerated in many diseases and pathways, it has yet to be addressed whether 4-HNE has the capacity to modulate oxidative stress-driven lipid peroxidation. Here we report an auto-regulatory mechanism of 4-HNE via modulation of the biological oxidant nitric oxide (NO). Utilizing LPS-activated macrophages to induce biological oxidant production, we demonstrate that 4-HNE modulates NO levels via inhibition of iNOS expression. We illustrate a proposed model of control of NO formation whereby at low concentrations of 4-HNE a negative feedback loop maintains a constant level of NO production with an observed inflection at approximately 1 mu M, while at higher 4-HNE concentrations positive feedback is observed. Further, we demonstrate that this negative feedback loop of NO production control is dependent on the Nrf2-Keap1 signaling pathway. Taken together, the careful regulation of NO production by 4-HNE argues for a more fundamental role of this lipid peroxidation product in normal physiology. (C) 2014 The Authors. Published by Elsevier B.V.