Asymmetric dimethylarginine downregulates sarco/endoplasmic reticulum calcium-ATPase 3 and induces endoplasmic reticulum stress in human umbilical vein endothelial cells

Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease. Endothelial cell injury and apoptosis may promote atherosclerosis and cardiovascular disease. The present study investigated the potential mechanisms of asymmetric dimethylarginine (ADMA)-induced apoptosis in human umbilical vein endothelial cells (HUVECs). It was demonstrated that ADMA decreased B-cell lymphoma-2 expression and increased cleaved-caspase-3 expression. Furthermore, terminal deoxynucleotidyl transferase (TdT)-mediated-digoxigenin-11-dUTP nick end labeling results indicated that ADMA induced apoptosis in HUVECs. These results suggest a potential mechanism of ADMA-induced endothelial cell injury. It was also verified that ADMA induced the expression of phosphorylated protein kinase RNA-like ER kinase, inositol requiring enzyme-1, C/EBP homologous protein and glucose-regulated protein, indicating activation of the endoplasmic reticulum (ER) stress response. Impaired function of sarco/endoplasmic reticulum calcium-ATPase (SERCA) is considered a major contributor to ER stress. It was demonstrated that ADMA induced a significant downregulation of SERCA3, however not SERCA2b. Overall, the results indicated that ADMA induced apoptosis in HUVECs, and that this effect was closely associated with induction of ER stress and decreased SERCA3 expression.