Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter

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Abstract

Objective—

LOX-1, a receptor for oxidized low-density lipoprotein, plays a critical role in atherosclerosis. Its expression is upregulated by pro-atherogenic stimuli, such as angiotensin II (Ang II). In this study, we explored LOX-1 transcriptional promoter activation in response to Ang II in human coronary artery endothelial cells (HCAECs).

Methods and Results—

We constructed full-length and deletion LOX-1 promoter mutants and examined their activation in response to Ang II in HCAECs. The Ang II (1 μmol/L for 24 hours) markedly induced LOX-1 promoter activity beyond the basal level, and a 116-bp fragment (between nt −2247 and −2131) was necessary for this induction. Within this 116-bp promoter fragment, there is a potential binding motif for transcription factor NF-κB. By EMSA, we observed the activation of NF-κB by Ang II. The critical role of NF-κB in Ang II–induced LOX-1 promoter activation was confirmed by mutagenesis assay, and further confirmed by blocking NF-κB activation with the NF-κB inhibitor caffeic acid phenethyl ester or NF-κB p65 siRNA.

Conclusion—

This study strongly suggests that Ang II, by activating NF-κB, induces LOX-1 promoter activation.

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