2. Academic Validation
  3. The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3

The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3

  • J Lipid Res. 2024 Jan 11:100499. doi: 10.1016/j.jlr.2024.100499.
Si Chen 1,  Jian-Jun Gao 1,  Yu-Jia Liu 1,  Zhi-Wei Mo 1,  Fang-Yuan Wu 2,  Zuo-Jun Hu 3,  Yue-Ming Peng 1,  Xiao-Qin Zhang 2,  Zhen-Sheng Ma 1,  Ze-Long Liu 1,  Jian-Yun Yan 4,  Zhi-Jun Ou 5,  Yan Li 6,  Jing-Song Ou 7
Affiliations

Affiliations

  • 1 Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China.
  • 2 National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China; Division of Hypertension and Vascular Diseases, Department of Cardiology, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China.
  • 3 National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China; Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China.
  • 4 Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, 510080, P.R. China.
  • 5 National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China; Division of Hypertension and Vascular Diseases, Department of Cardiology, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China. Electronic address: Zhijunou@163.com.
  • 6 Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China. Electronic address: li_yan_lee@126.com.
  • 7 Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, P.R. China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, P.R. China. Electronic address: oujs2000@163.com.
PMID: 38218337 DOI: 10.1016/j.jlr.2024.100499
Abstract

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell Ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•-), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), Glutathione Peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•-, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of Ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell Ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Keywords

Atherosclerosis; CD36; Endothelial function; Fatty acid binding protein-3; Oxidized lipids; PGPC.

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