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

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

  • Exp Cell Res. 2019 Jun 15;379(2):191-202. doi: 10.1016/j.yexcr.2019.04.002.
Sanjiu Yu 1,  Laiping Zhang 2,  Chuan Liu 3,  Jie Yang 4,  Jihang Zhang 5,  Lan Huang 6
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: sanjiuyu09@163.com.
  • 2 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: laipingzhang@163.com.
  • 3 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: liuchuan19821207@163.com.
  • 4 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: yangjie0818@hotmail.com.
  • 5 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: zhang.zjh@qq.com.
  • 6 Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: huanglan260@126.com.
PMID: 30970236 DOI: 10.1016/j.yexcr.2019.04.002
Abstract

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.

Keywords

Atherosclerosis; Calcium; Endothelial cell apoptosis; Mitochondria-associated ER membrane; Mitochondrial dysfunction; PACS2.

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