Hypoxia Induces High-Mobility-Group Protein I(Y) and Transcription of the Cyclooxygenase-2 Gene in Human Vascular Endothelium

Abstract—Cyclooxygenases catalyze a rate-limiting step in the synthesis of vascular endothelial prostaglandins. Expression of the inducible cyclooxygenase-2 (COX-2) gene is increased by hypoxia in human vascular endothelial cells via the nuclear factor (NF)-κB p65 transcription factor, which is necessary but not sufficient to fully induce COX-2 transcription in response to hypoxia. After finding that cytoplasmic NF-κB p65 and IκBα (an inhibitory protein that binds NF-κB p65 precursors) levels are not changed by hypoxia, we hypothesized that other factors might play a role in regulating the COX-2 promoter, like the high-mobility-group (HMG) I(Y) family of proteins, which features multiple A·T hooks and is associated with NF-κB–mediated transactivation. Nuclear protein obtained from human umbilical vein endothelial cells (HUVECs) was supplemented with HMG I(Y) during electrophoretic mobility shift assays using an NF-κB-3′ element probe. These data suggested that HMG I(Y) proteins interact with NF-κB p65 to ...