Silica nanoparticles induced endothelial apoptosis via endoplasmic reticulum stress-mitochondrial apoptotic signaling pathway.

Along with their extensively application, human exposure to amorphous silica nanoparticles (SiNPs) has highly increased. Accumulative toxicological researches have provided the scientific correlation between SiNPs exposure and cardiovascular diseases. Endothelial apoptosis is vital in the initiation and progression of atherosclerosis. However, molecular details between SiNPs and endothelial apoptosis remain unidentified. Here, we investigated the uptake and toxic mechanism of SiNPs using HUVECs (Human umbilical vein endothelial cells). Consequently, at 24-h exposure, SiNPs were located freely or within membrane-bound agglomerates in the cytosol, especially in mitochondrial and endoplasmic reticulum (ER) regions with swelled mitochondria, cristae rupture or aggregated ER. Further, we demonstrated that SiNPs induced endothelial apoptosis as evidenced by the Annexin V/PI staining and flow cytometry determination. In line with the ultrastructure alterations, SiNPs triggered mitochondrial ROS generation, ΔΨm collapse, cytosolic Ca2+ overload, as well as ER stress confirmed by enhanced ER staining, up-regulated GRP78/BiP and XBP1 splicing. More notably, in line with the induction of apoptosis, SiNPs-induced ER stress-associated activation of CHOP, caspase-12, and IRE1α/JNK pathways, which may regulate the BCL2 family member as evidenced by a increased proapoptotic BAX while a decline of anti-apoptotic Bcl-2, ultimately facilitate the mitochondria-mediated apoptotic caspase cascade as confirmed by the upregulated expressions of cytochrome c, Caspase-9 and -3. Altogether, our results indicated the activation of ER stress-mitochondria cascade-mediated apoptotic pathways may be a key mechanism among the SiNPs-induced endothelial apoptosis.