Endoplasmic reticulum stress-dependent oxidative stress mediated vascular injury induced by silica nanoparticles in vivo and in vitro

The safety concern on silica nanoparticles (SiNPs) is rapidly expanding with its increased production for industrial, environmental, and pharmaceutical applications. We have reported SiNPs induced endothelial dysfunction, which potentially precedes atherosclerosis and ultimately contributes to cardiovascular disease. However, its molecular mechanisms haven't been clearly determined. Here, we observed the subchronic exposure of SiNPs induced vascular injury, accompanied by oxidative stress, ER stress and apoptosis in the artery. Further, their detailed interactions in SiNPs-induced vascular injury were investigated in vitro. SiNPs were internalized and deposited the intracellular ER region of human umbilical vein endothelial cells (HUVECs), and triggered the activation of ER stress as validated by the up-regulated PERK/eIF2 alpha/ATF4, IRE1/XBP1 and ATF6 pathways. Mechanistic analyses by using ER stress inhibitor (4-PBA or Salubrinal) and antioxidant agent N-acetylcysteine (NAC) confirmed an ER stress-dependent oxidative stress and apoptosis induced by SiNPs, which mediated the consequent vascular endothelial injury, ultimately contributing to vascular disease.