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Background —We demonstrated earlier that angiotensin II (Ang II), by AT1 receptor activation, upregulates oxidized LDL (ox-LDL) endothelial receptor LOX-1 gene expression and uptake of ox-LDL in human coronary artery endothelial cells (HCAECs). In this study, we investigated the regulation of Ang II receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive transcription factor NF-κB in this process.Methods and Results —HCAECs were incubated with ox-LDL for 24 hours. Ox-LDL (10 to 40 μg protein/mL) upregulated AT1R but not AT2R, mRNA, or protein. Ox-LDL degraded IκBα in cytoplasm and activated transcription factor NF-κB (P65) in HCAEC nuclear extract. Treatment of cells with the antioxidant α-tocopherol (10 to 50 μmol/L) attenuated ox-LDL–mediated degradation of IκBα and activation of NF-κB (P65) and inhibited the upregulation of AT1R mRNA and protein. The role of NF-κB signal transduction was further examined by use of an NF-κB inhibitor, caffeic acid phenethyl ester (CAPE). Pretreatment of cells with CAPE inhibited ox-LDL–mediated degradation of IκBα and NF-κB activation and inhibited ox-LDL–induced upregulation of AT1R expression. Incubation of cells with both ox-LDL and Ang II increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone. α-Tocopherol as well as the specific AT1R blocker CV11974 (candesartan) attenuated the cell-injurious effects of ox-LDL.Conclusions —These observations suggest an important role of ox-LDL–mediated AT1R upregulation in cell injury. In this process, NF-κB activation seems to play a critical role in signal transduction. These findings provide a basis for the use of antioxidants and AT1R blockers in designing therapy of atherosclerosis.

Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells