Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal.
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.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
ISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Stereoisomerism
- Signal Transduction
- Oxidative Stress
- Oxidants
- Nitric Oxide Synthase Type II
- Nitric Oxide
- NF-E2-Related Factor 2
- Mice, Inbred C57BL
- Mice
- Macrophages
Citation
Published In
DOI
ISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Stereoisomerism
- Signal Transduction
- Oxidative Stress
- Oxidants
- Nitric Oxide Synthase Type II
- Nitric Oxide
- NF-E2-Related Factor 2
- Mice, Inbred C57BL
- Mice
- Macrophages