Oxidized lipid derived aldehyde, 4‐hydroxy‐trans‐2‐nonenal causes vascular inflammation by inducing endoplasmic reticulum stress

Abstract

Oxidized lipoproteins‐derived aldehydes, such as 4‐hydroxy‐trans‐2‐nonenal (HNE) increase endothelial activation, however, mechanisms that mediate the effects of lipid oxidation products on the endothelium remain unclear. We observed HNE modified ER proteins in atherosclerotic lesions of apoE‐null mice. In vitro, treatment of endothelial cells (EC) and macrophages with HNE led to the modification of several proteins that colocalize with the endoplasmic reticulum (ER). HNE also caused the splicing of XBP‐1, an increase in the phosphorylation of PERK and eIF2á, and induction of ATF3 and ATF4. Phosphorylation of eIF2á by HNE was prevented by transfection with PERK siRNA. Treatment with HNE was also associated with a significant increase in the expression of ER chaperones, GRP78 and HERP. Pre‐treatment with a chemical chaperone, phenylbutyric acid (PBA) or adenoviral transfection with ATF6 attenuated HNE‐induced monocyte adhesion and IL‐8 induction. IL‐8 induction was also prevented by IRE1 siRNA. Moreover, PBA and taurine‐conjugated ursodeoxycholic acid (TUDCA) attenuated HNE‐induced leukocyte rolling and their firm adhesion to the endothelium in rat cremaster muscle. These data suggest that endothelial activation by HNE is mediated in part by ER stress. ER stress, induced by oxidized lipids may be a significant cause of vascular inflammation during atherogenesis.