PATHWAYS TO 4-HYDROXYNONENAL

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

The long-term objective of this project is to elucidate the basis of aldehyde formation during lipid[unreadable] peroxidation, and thus advance our understanding of the etiology of atherogenesis and other diseases[unreadable] associated with oxidative stress. 4-Hydroxy-nonenal (HNE) and related aldehydes are among the most[unreadable] important reactive agents formed from polyunsaturated fatty acids during autoxidation yet the reactions[unreadable] underlying their synthesis are not at all well understood. We have now developed a detailed hypothesis[unreadable] implicating inter-molecular peroxyl radical reactions as a main pathway leading to HNE and related[unreadable] aldehydes. This is associated with cross-molecular epoxidations that can generate additional novel and[unreadable] bioactive products. The proposed mechanisms will be examined utilizing identification of intermediates by[unreadable] HPLC, UV, mass spectrometry, and NMR, and using stable isotope labeling to follow the reaction pathway[unreadable] and study the mechanisms of oxygen transfer. The Specific Aims are to investigate:[unreadable] 1. Inter-molecular mechanisms of 4-hydroperoxy-nonenal formation: peroxyl radical-dependent pathways[unreadable] 2. Aldehyde and epoxide formation during autoxidation of natural substrates[unreadable] 3. Biological implications of novel lipid peroxidation-derived products[unreadable] An important component of these studies in Aims 1 and 2 is the proposed isolation of individual species of[unreadable] cross-linked fatty acids and phospholipids, their precise structural and stereochemical characterization, and[unreadable] a detailed analysis of their degradative products, postulated to include the HNE-related aldehydes. The[unreadable] activity of novel epoxy-hydroperoxide products of lipid peroxidation will be assessed as PPAR ligands, and[unreadable] vitamin C-HNE adducts will be characterized and quantified (Aim 3).[unreadable] Elucidation of the biosynthesis of these reactive aldehydes has practical applications in defining the[unreadable] parameters that influence the production of aldehydes, identification of novel and reactive chemical species[unreadable] involved in the synthetic pathways, and improving the assessment of peroxide tone/oxidative stress in[unreadable] tissues.