High expression of active ATF6 aggravates endoplasmic reticulum stress-induced vascular endothelial cell apoptosis through the mitochondrial apoptotic pathway

Activating transcription factor 6 (ATF6), one of three sensor proteins in the endoplasmic reticulum (ER), is an important regulatory factor in the ER stress-induced apoptosis pathway. Although recent studies have made some progress in elucidating the regulation mechanism of ATF6, the specific regulatory mechanism of ER stress-induced vascular endothelial cell (VEC) apoptosis is still unclear. The present study was designed to investigate the role of ATF6 in VECs under thapsigargin (TG)-induced ER stress. ATF6 (1–366aa; ATF6 high-expressed plasmid) and ATF6 (151-366aa; plasmid without transcriptional activity) were transfected into VECs to yield an ATF6 high-expression model and a positive control model, respectively. High expression of ATF6 decreased viability and aggravated ER stress-induced apoptosis in VECs. Increased expression of apoptosis-related genes, including those encoding caspase-3, caspase-9, C/EBP homologous protein (CHOP), cytochrome c and B-cell lymphoma-associated protein X (Bax)/B-cell lymphoma (Bcl-)2, was detected by polymerase chain reaction and western blotting in the ATF6 (1-366aa) + TG group. No significant effect of TG treatment and high ATF6 expression was indicated on the expression of death receptor-related genes, including those encoding caspase-8 and Fas. The results demonstrated that high expression of activated ATF6 aggravates ER stress-induced VEC apoptosis through the mitochondrial apoptotic pathway. Furthermore, in response to ER stress, ATF6 upregulates the expression of caspase-3, caspase-9, CHOP, cytochrome c and Bax/Bcl-2.