4-Hydroxynonenal in the Pathomechanisms of Oxidative Stress

Abstract

Here we review the current knowledge on the biochemistry and molecular pathology of oxidative stress with specific regard to a major aldehydic end-product stemming from peroxidation of biomembranes, that is 4-hydroxynonenal (HNE). This multifunctional molecule, which derives from the most represented class of polyunsaturated fatty acids in the membranes, is potentially able to undergo a number of reactions with proteins, phospholipids, and nucleic acids. Despite an active metabolism in most of the cell types, HNE can be detected in several biological tissues by means of sufficiently precise methods, although with different sensitivity. In particular, relatively high steady-state levels of HNE are often detectable in a large variety of human disease processes, pointing to some involvement of the aldehyde in their pathogenesis. Among the prominent pathobiochemical effects of HNE is its remarkable stimulation of fibrogenesis and inflammation, which indicates a potential contribution of the aldehyde to the pathogenesis of several chronic diseases, whose progression is indeed supported by inflammatory reactions and characterized by fibrosis. Further, of interest appears to be the ability of HNE to modulate cell proliferation through interference with the activity of cyclins and protein kinases and with the apoptotic machinery. Finally, on the basis of the already achieved evidence, pursuing investigation of the role of HNE in signal transduction and gene expression seems very promising.

Overexpression of Aldehyde Dehydrogenase-2 Attenuates Neurotoxicity Induced by 4-Hydroxynonenal in Cultured Primary Hippocampal Neurons

“…Evidences from previous researches (Poli and Schaur 2000;Nakashima et al 2003) also indicated that the 4HNE is a key mediator of oxidative stress-induced cell death. 4HNE modulates several mechanisms inducing apoptosis such as, increasing the ROS production and altering mitochondrial respiratory and signal transductions.…”

“…Effect of ALDH2 on 4HNE-Induced Increase in Intracellular Reactive Oxygen Species Level 4-Hydroxynonenal has been suggested to be a key mediator of oxidative stress-induced cell death and to induce mitochondrial oxidative stress (Poli and Schaur 2000;Raza and John 2006). In order to examine whether the inhibitory effect of ALDH2 on the toxicity of 4HNE is mediated by decreasing ROS level, neurons were treated with 10 lM 4HNE for 24 h, and the levels of ROS were measured using DCF fluorescence.…”

Hepatotoxicity of Reactive Aldehydes☆

“…Of primary concern is the ability to covalently modify cellular macromolecules. 4-HNE protein modifications have been implicated in the etiology of many disease states including mitochondrial dysfunction, atherosclerosis, Alzheimer's disease, diabetes, and alcoholic liver disease (Hartley et al, 1997;Poli and Schaur, 2000;Roede and Jones, 2010;Sampey et al, 2003). 4-HNE and 4-ONE also have the ability to modify nucleic acids and low levels of DNA adducts are abundant in both untreated rodent and human genomes (Sampey et al, 2003).…”

4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis

“…An increasing number of reports provide evidence of a causative involvement of this biogenic aldehyde in the pathogenesis of a great number of inflammatory and degenerative processes, including atherosclerosis, Alzheimer's and Parkinson's diseases, liver fibrosis, glomerusclerosis, chronic obstructive bronco-pulmonary diseases and, last but not the least, atherosclerosis (see for a review [4]). With special regard to HNE potential involvement in the pathogenesis of atherosclerosis, this has been corroborated by consistent detection of the aldehyde in both oxLDL [3] and fibrotic plaque in humans [5].…”