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Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) apoptosis is the initial step of atherogenesis and associated with Ca 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 Ca overload by mediating ER-mitochondria Ca 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 Ca 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 Ca, 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 Ca elevation, implicating that PACS2 may be a promising therapeutic target for atherosclerosis.
This article was published in the following journal.
Name: Experimental cell research
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A member of the TNF receptor family that was initially identified as a DEXAMETHASONE-induced protein from a T-CELL line. It may play a role in regulating APOPTOSIS and modulating immune response by T-lymphocytes. Signaling by the activated receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.
A flavoprotein that functions as a powerful antioxidant in the MITOCHONDRIA and promotes APOPTOSIS when released from the mitochondria. In mammalian cells AIF is released in response to pro-apoptotic protein members of the bcl-2 protein family. It translocates to the CELL NUCLEUS and binds DNA to stimulate CASPASE-independent CHROMATIN condensation.
An SHC-signaling adaptor protein that transduces PHOSPHOTYROSINE-dependent signals downstream of RECEPTOR PROTEIN-TYROSINE KINASES and non-receptor tyrosine kinases. It is required for TGF-BETA-induced CELL MIGRATION; NEOLPASM INVASION; and METASTASIS of BREAST NEOPLASMS; its SH2 DOMAIN is essential for tumor survival. It also functions in signaling downstream of ANGIOPOIETIN RECEPTOR TIE-2, regulating the migration of ENDOTHELIAL CELLS; and PHYSIOLOGIC NEOVASCULARIZATION.
PKC beta encodes two proteins (PKCB1 and PKCBII) generated by alternative splicing of C-terminal exons. It is widely distributed with wide-ranging roles in processes such as B-cell receptor regulation, oxidative stress-induced apoptosis, androgen receptor-dependent transcriptional regulation, insulin signaling, and endothelial cell proliferation.
An APOPTOSIS-regulating protein that is structurally related to CASPASE 8 and competes with CASPASE 8 for binding to FAS ASSOCIATED DEATH DOMAIN PROTEIN. Two forms of CASP8 and FADD-like apoptosis regulating protein exist, a long form containing a caspase-like enzymatically inactive domain and a short form which lacks the caspase-like domain.