4-Hydroxynonenal As a Biological Signal: Molecular Basis and Pathophysiological Implications

Reactive oxygen intermediates (ROI) and other pro-oxidant agents are known to elicit, in vivo and in vitro, oxidative decomposition of ω-3 and ω-6 polyunsaturated fatty acids of membrane phospholipids (i.e., lipid peroxidation). This leads to the formation of a complex mixture of aldehydic end-products, including malonyldialdehyde (MDA), 4-hydroxy-2,3-nonenal (HNE), and other 4-hydroxy-2,3-alkenals (HAKs) of different chain length. These aldehydic molecules have been considered originally as ultimate mediators of toxic effects elicited by oxidative stress occurring in biological material. Experimental and clinical evidence coming from different laboratories now suggests that HNE and HAKs can also act as bioactive molecules in either physiological and pathological conditions. These aldehydic compounds can affect and modulate, at very low and nontoxic concentrations, several cell functions, including signal transduction, gene expression, cell proliferation, and, more generally, the response of the target cell(s). In this review article, we would like to offer an up-to-date review on this particular aspect of oxidative stress - dependent modulation of cellular functions - as well as to offer comments on the related pathophysiological implications, with special reference to human conditions of disease.