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

Abstract

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.

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

“…High levels of asymmetric dimethylarginine (ADMA) have been associated with an increased cardiovascular risk [ 58 , 97 , 98 ]. Our systematic literature search revealed one study that examined ADMA in the context of endothelial dysfunction ( Table 1 ), showing that in vitro treatment of endothelial cells with ADMA-induced apoptosis [ 58 ].…”

“…High levels of asymmetric dimethylarginine (ADMA) have been associated with an increased cardiovascular risk [ 58 , 97 , 98 ]. Our systematic literature search revealed one study that examined ADMA in the context of endothelial dysfunction ( Table 1 ), showing that in vitro treatment of endothelial cells with ADMA-induced apoptosis [ 58 ]. Endoplasmic reticulum (ER) stress increased as cytosolic Ca 2+ levels rose and ER Ca 2+ levels declined due to the inhibition of the sarco/endoplasmic reticulum calcium-ATPase [ 58 ].…”

“…Our systematic literature search revealed one study that examined ADMA in the context of endothelial dysfunction ( Table 1 ), showing that in vitro treatment of endothelial cells with ADMA-induced apoptosis [ 58 ]. Endoplasmic reticulum (ER) stress increased as cytosolic Ca 2+ levels rose and ER Ca 2+ levels declined due to the inhibition of the sarco/endoplasmic reticulum calcium-ATPase [ 58 ]. Further, increased phosphorylation of protein kinase RNA-like ER kinase (PERK) and inositol requiring enzyme-1 (IRE1) was observed, both known to be associated with cell death [ 99 , 100 ].…”

“…Additionally, ADMA treatment of endothelial cells enhanced levels of the ER chaperone 78-kDa glucose-regulated protein (GRP78/BiP), indicating defective protein folding and degradation. Together with decreased levels of apoptosis inhibitor BCL-2 and increased cleavage of caspase-3, a critical executioner of apoptosis, ADMA was shown to be an inducer of apoptosis in endothelial cells [ 58 ].…”

Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells

“…It is known that ATP2A3 controls Ca 2+ transport and that its aberrant expression can cause ER stress [28, 29]. Thus we analyzed the effect of ATP2A3 overexpression on ER stress in prostate cancer.…”