Abstract
This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress.
Highlights
A review of Catala [3] provide a synopsis of identified effects of HNE and other hydroxy-alkenals and oxidized phospholipids on cell signaling, from their intracellular production to their action as intracellular messengers, up to their influence on transcription factors and gene expression
Similar to AKR7A2, these findings suggest that rat AKR1B10 (R1B10) serves antioxidant defenses in rat tissues which holds true for rat AKR1C15, which is upregulated by HNE and protects endothelial cells from HNE mediated cell damage [72]
By investigating the ability of BSA modified by lipid peroxidation to compete with AcLDL, Kumano-Kuramochi et al, 2012 showed that HNE-modified proteins most potently inhibited the uptake of AcLD, that both the modification of BSA and the oxidation of LDL resulted in the formation of HNE-histidine Michael adducts, that the HNE-histidine adduct inhibited the uptake of AcLDL in a dose-dependent manner, and that the HNE-histidine adduct stimulated the formation of ROS and activated extracellular-signal-regulated kinase 1/2 (ERK 1/2) and NFκB initiating endothelial dysfunction and leading to atherosclerosis [208]
Summary
In this chapter a brief overview will be presented on the molecular mechanisms underlying lipid peroxidation. The stereoselective formation of HNE-cyteine adducts was demonstrated in the redox-regulatory protein thioredoxin, the active site at Cys showing a preference for R-HNE cysteine adducts These findings provide insight into structural aspects of lipid peroxidation product/HNE—based sulfhydryl modification and the chemical characterization of protein S-associated aldehydes in vitro and in vivo. In this context it is worth to mention that an efficient, enantioselective synthesis of (R)- and (S)-HNE has been worked out recently by Komisarski et al [32]. HNE and its glutathione conjugates are able to regulate oxidative stress related transcription factors such as NFκB and AP-1 by addressing protein kinase cascade mediated stress signaling This transcriptional activation leads to an upregulated expression of several genes involved in cell differentiation and cell death control. HNE stimulates the Nrf (NFE2-related factor 2) mediated upregulation of γ-glutamylcysteine ligase and the core subunit of the high-affinity cystine transporter Xc(-) yielding a 1.45-fold shift of intracellular GSH levels
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