Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal.

Journal Article (Journal Article)

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 µM, 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.

Full Text

Duke Authors

Cited Authors

  • Gatbonton-Schwager, TN; Sadhukhan, S; Zhang, G-F; Letterio, JJ; Tochtrop, GP

Published Date

  • 2014

Published In

Volume / Issue

  • 2 /

Start / End Page

  • 755 - 763

PubMed ID

  • 25009777

Pubmed Central ID

  • PMC4085345

International Standard Serial Number (ISSN)

  • 2213-2317

Digital Object Identifier (DOI)

  • 10.1016/j.redox.2014.04.009


  • eng

Conference Location

  • Netherlands