Proatherogenic effects of 4-hydroxynonenal

Abstract

Among the various mechanisms involved in atherogenesis, the oxidative theory of atherosclerosis relies on the oxidation of low density lipoprotein (LDL) in the vascular wall and their implication in the formation of early atherosclerotic lesions. Reactive oxygen species (ROS) and oxidants generated by activated endothelium, initiate LDL oxidation in the intima, which generates a huge variety of lipid peroxidation products (LPPs), exhibiting atherogenic, pro-inflammatory and pro-apoptotic properties. Reactive carbonyl compounds (RCCs), are a family of highly reactive agents generated during polyunsaturated fatty acid (PUFA) peroxidation. RCCs covalently bind to nucleophilic group of proteins, peptides, phospholipids and nucleic acids, thereby generating a “carbonyl stress”. Among RCCs, 4-hydroxy-2-nonenal (HNE) exerts its atherogenic effects through several mechanisms, by targeting lipoproteins or cellular components. HNE generated during LDL oxidation is able to form HNE-apoB adducts, which are recognized by scavenger-receptors of macrophagic cells, thereby leading to foam cell formation. HNE can be released during the degradation of oxLDL, or generated through oxidative stress and PUFA peroxydation in cell membranes. The biological effects of HNE on vascular cells depend on its local concentration and on the expression of detoxifying systems, such as glutathione S-transferase, aldose reductase, and aldehyde dehydrogenase (ALDH), which rapidly neutralize and remove HNE from cells. Physiological concentrations (0.1-1 µmol/L) of HNE induce hormetic and adaptive responses, and transcription factors (Nrf2) that increase cell resistance to oxidative attack and other stresses, while moderate HNE concentrations, (1 to 10 µmol/L), trigger the accumulation of HNE-adducts and a variety of biological responses, such as inflammation and cell proliferation. Higher HNE concentrations, (above 10-20 µmol/L), induce cell dysfunction and apoptosis. However, important variations are observed in atherosclerotic lesions, from the lipid core to the periphery of the plaque, with very different local outcomes. HNE can modify signaling proteins involved in atherosclerotic plaque remodeling, particularly growth factor receptors (PDGFR, EGFR), cell cycle proteins, mitochondrial and endoplasmic reticulum components or extracellular matrix proteins, which progressively alters smooth muscle cell proliferation, angiogenesis and induces apoptosis. HNE-adducts accumulate in the lipidic necrotic core of advanced atherosclerotic lesions and may locally contribute to macrophage and smooth muscle cell apoptosis, which contributes to plaque destabilization and rupture, thereby increasing the risk of athero-thrombotic events.