Arsenite Induces Vascular Endothelial Cell Dysfunction by Activating IRE1α/XBP1s/HIF1α-Dependent ANGII Signaling

: Chronic arsenic exposure is associated with the development of several cardiovascular (CV) diseases, including hypertension, carotid atherosclerosis and microvascular abnormalities. Upregulation of systemic and aortic angiotensin II (ANGII) signaling has been proposed to contribute to arsenic-induced vascular dysfunction. However, the underlying mechanisms of ANGII signaling augmentation and of the attendant pathological effects on the CV system induced by arsenic remain largely unknown. Here, we reported that exposure of human umbilical vein endothelial cells (HUVECs) to arsenite resulted in elevation of angiotensinogen (AGT, the precursor of ANGII), angiotensin-converting enzyme (ACE, the enzyme critical for ANGII generation), and ANGII type I receptor (AT1R) synthesis as well as increased ANGII production. Further investigations showed that endoplasmic reticulum (ER) stress was induced and activation of the IRE1α/XBP1s arm of the unfolded protein response was responsible for the augmented ACE/ANGII/AT1R axis components in arsenite-treated HUVECs. Moreover, XBP1s promoted HIF1α accumulation, and inducible XBP1s/HIF1α complex formation was required to drive the transcription of AGT, ACE, and AT1R under arsenite exposure. Ablation of IRE1α/XBP1s/HIF1α-dependent ANGII signaling activation inhibited oxidative stress and proinflammatory response induced in HUVECs by arsenite. These results thus have revealed the novel role of ER stress-coupled HIF1α pathway activation in mediating ANGII-dependent endothelial cell dysfunction upon arsenite exposure. Therefore, searching for strategies to alleviate endothelial ER stress or ANGII signaling might be helpful for managing arsenite-induced CV disorders.