PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca2+ elevation.

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) apoptosis is the initial step of atherogenesis and associated with Ca2+ overload. Mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), regulated by tethering proteins such as phosphofurin acidic cluster sorting protein 2 (PACS2), is essential for mitochondrial Ca2+ overload by mediating ER-mitochondria Ca2+ transfer. In our study, we aimed to investigate the role of PACS2 in ox-LDL-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. Ox-LDL dose- and time-dependently increased cell apoptosis concomitant with mitochondrial Ca2+ elevation, mitochondrial membrane potential (MMP) loss, reactive oxygen species (ROS) production, and cytochrome c release. Silencing PACS2 significantly inhibited ox-LDL-induced cell apoptosis at 24 h in addition to the effects of ox-LDL on mitochondrial Ca2+, MMP, and ROS at 2 h. Besides, ox-LDL promoted PACS2 localization at mitochondria as well as ER-mitochondria contacts at 2 h. Not only that, ox-LDL upregulated PACS2 expression at 24 h. Furthermore, silencing PACS2 inhibited ox-LDL-induced mitochondrial localization of PACS2 and MAM formation at 24 h. Altogether, our findings suggest that PACS2 plays an important role in ox-LDL-induced EC apoptosis by regulating MAM formation and mitochondrial Ca2+ elevation, implicating that PACS2 may be a promising therapeutic target for atherosclerosis.