title: Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal.
abstract: 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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Tonibelle N
authors.initials: TN
authors.lastname: Gatbonton-Schwager
authors.affiliation: Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Sushabhan
authors.initials: S
authors.lastname: Sadhukhan
authors.affiliation: Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA ; Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA ; Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Tochtrop
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D015227:Lipid Peroxidation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000138:chemical synthesis / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016877:Oxidants; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C027576:4-hydroxy-2-nonenal
keywords: 4-HNE; Nrf2; iNOS; lipid peroxidation; nitric oxide