Hiv Protease Inhibitors Induce Er Stress And Apoptosis In Human Endothelial Cells

Endothelial dysfunction/injury represents a key step in the early stage of atherogenesis. Recent studies have shown that HIV protease inhibitors (PIs) induce endothelial dysfunction, but the underlying molecular mechanism remains unclear. Our previous studies have shown that HIV PI‐induced ER stress and activation of the unfolded protein response (UPR) represents an important cellular mechanism by which HIV PIs disrupt lipid metabolism and induce inflammation in hepatocytes and macrophages. The aim of this study was to determine if HIV PIs also induce ER stress and apoptosis in human endothelial cells. Methods Human umbilical vein endothelial cells (HUVECs) were treated with individual HIV PIs for various time periods. The mRNA and protein levels of ER stress responsive genes were measured by real‐time RT‐PCR and Western blot analysis, respectively. The apoptosis was detected by fluorescence microscopy using Annexin V‐FITC/propidium iodide. The protein levels of TNF‐α, IL‐6, and MCP‐1 were determined by ELISA. Results Both lopinavir and ritonavir dose‐dependently activated the UPR, increased IL‐6 and MCP‐1 expression, and induced apoptosis in HUVECs. But amprenavir had no significant effect. Conclusions HIV PI‐induced ER stress response and activation of the UPR may represent a critical molecular mechanism underlying HIV PI‐associated endothelial dysfunction and atherogenesis.