Acid sphingomyelinase mediates oxidized-LDL induced apoptosis in macrophage Via endoplasmic reticulum stress

Min Zhao, Wei Pan, Rui Zheng Shi, Yong Ping Bai, Bo Yang You, Kai Zhang, Qiong Mei Fu, Edward H. Schuchman, Xing Xuan He, Guo Gang Zhang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Aim: Macrophage apoptosis is a vital event in advanced atherosclerosis, and oxidized low-density lipoprotein (ox-LDL) is a major contributor to this process. Acid sphingomyelinase (ASM) and ceramide are also involved in the induction of apoptosis, particularly in macrophages. Our current study focuses on ASM and investigates its role in ox-LDL-induced macrophage apoptosis. Methods: Human THP-1 and mouse peritoneal macrophages were cultured in vitro and treated with ox-LDL. ASM activity and ceramide levels were quantified using ultra performance liquid chromatography. Protein and mRNA levels were analyzed using Western blot analysis and quantitative realtime PCR, respectively. Cell apoptosis was determined using Hoechst staining and flow cytometry. Results: Ox-LDL-induced macrophage apoptosis was triggered by profound endoplasmic reticulum (ER) stress, leading to an upregulation of ASM activity and ceramide levels at an early stage. ASM was inhibited by siRNA or desipramine (DES), and/or ceramide was degraded by recombinant acid ceramidase (AC). These events attenuated the effect of ox-LDL on ER stress. In contrast, recombinant ASM upregulated ceramide and ER stress. ASM siRNA, DES, recombinant AC, and ER stress inhibitor 4-phenylbutyric acid were blocked by elevated levels of C/EBP homologous protein (CHOP); ox-LDL induced elevated levels of CHOP. These events attenuated macrophage apoptosis. Conclusion: These results indicate that ASM/ceramide signaling pathway is involved in ox-LDLinduced macrophage apoptosis via ER stress pathway.

Original languageEnglish
Pages (from-to)1111-1125
Number of pages15
JournalJournal of Atherosclerosis and Thrombosis
Volume23
Issue number9
DOIs
StatePublished - 2016

Keywords

  • Acid sphingomyelinase
  • Atherosclerosis
  • Ceramide
  • ER stress
  • Macrophage apoptosis

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