The lipid peroxidation product 4‐hydroxy‐trans‐2‐nonenal (HNE) promotes unique ER stress responses

Abstract

Aldehydes such as HNE are major end products of lipid peroxidation. Protein-HNE adducts accumulate in tissues under oxidative stress; however, the mechanisms by which lipid peroxidation-derived aldehydes incite tissue injury remain unclear. We tested the hypothesis that electrophilic aldehydes trigger the unfolded protein response. Exposure of rat aortic smooth muscle cells to HNE (25–200 μM) led to the appearance of multiple anti-protein-HNE immunopositive proteins. Two-dimensional Western blots, immunoprecipitation, and MALDI-TOF MS analyses demonstrated the modification of several ER proteins including Grp78, Grp58, PDI, and reticulocalbin. Exposure to HNE led to activation of the PERK pathway. HNE activated p38 and JNK and increased the expression of HO-1. Pretreatment with Tiron prevented HNE-induced PERK phosphorylation, and inhibition of JNK abrogated HO-1 induction. Balloon-injured rat carotid arteries showed increased neointimal immunoreactivity with anti-protein-HNE antibodies and anti-phospho-PERK antibodies. These results suggest that HNE causes ER stress and activates the alarm and adaptive phases of the unfolded protein response via redox-sensitive mechanisms. These effects of HNE could contribute to the proinflammatory effects of oxidized lipids and to the induction of the unfolded protein response in atherosclerotic lesions and restenotic vessels.