[No authors listed]
Vascular endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) has been implicated in the early stages of the pathogenesis of atherosclerosis. In this study, we incubated bovine aortic endothelial cells (BAECs) with ox-LDL (100 µg/ml) in order to induce endoplasmic reticulum (ER) stress and to investigate the regulation of endothelial nitric oxide synthase (eNOS). Within 4 h of exposure, ox-LDL rapidly induced ER stress, as demonstrated by the measurements of proline-rich extensin-like receptor kinase (PERK) and glucose-regulated protein (GRP)78. ox-LDL induced the rapid dephosphorylation of eNOS at Ser1179 and a subsequent decrease in eNOS activity. This effect appeared to be highly specific as no change was observed in the levels of phosphorylated eNOS at Thr497 or eNOS protein. Of note, a simultaneous decrease was also observed in the active (phosphorylated) form of Akt (Thr308/Ser473), which has been demonstrated to phosphorylate eNOS at Ser1179. Further analysis indicated that Brefeldin A (BFA), an ER stress-inducing reagent, induced the rapid dephosphorylation of Akt and eNOS at Ser1179. 4-Phenylbutyric acid (PBA), an inhibitor of ER stress, blocked the ox-LDL-induced dephosphorylation of Akt and eNOS. Furthermore, JTX20, a lectin-like ox-LDL receptor-1 (LOX-1) blocking antibody significantly eliminated the ability of ox-LDL to mediate the dephosphorylation of eNOS and Akt. Our results indicate that the downregulation of eNOS by ox-LDL, as driven by LOX-1-mediated ER stress, is associated with the PI3K-Akt-eNOS signaling pathway.
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