Pigment Epithelial‐Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia

Author:

Wang Haiping1,Yang Yanfang12,Yang Ming1,Li Xinghui1,Tan Jing1,Wu Yandi1,Zhang Yuling3,Li Yuanlong1,Hu Bo4,Deng Shijie1,Yang Fengmin1,Gao Saifei1,Li Hui1,Yang Zhenyu1,Chen Hui5,Cai Weibin1

Affiliation:

1. Laboratory Animal Center and Department of Biochemistry Institute of Guangdong Engineering and Technology Research Center for Disease‐Model Animals Zhongshan School of Medicine Sun Yat‐sen University Guangzhou China

2. Department of Prenatal Diagnosis Maoming People's Hospital Maoming Guangdong China

3. Department of Cardiology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China

4. Department of Laboratory Medicine The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou China

5. Department of Obstetrics and Gynecology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China

Abstract

Background Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid ( FA ) transport. Pigment epithelial‐derived factor ( PEDF ) is an important regulator in lipid metabolism. We hypothesized that PEDF is involved in endothelium‐mediated FA uptake under hyperlipidemic conditions. Methods and Results Circulating PEDF levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum PEDF levels were confirmed in both wild‐type and apolipoprotein E–deficient mice fed a long‐term high‐fat diet. Apolipoprotein E–deficient/PEDF‐deficient mice were generated by crossing PEDF‐deficient mice with apolipoprotein E–deficient mice, and then mice were fed with 24, 36, or 48 weeks of high‐fat diet. Greater increases in body fat and plasma lipids were displayed in PEDF ‐deficient mice. In addition, PEDF deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno‐associated virus encoding PEDF exerted opposite effects. Mechanistically, PEDF inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor‐1 and neuropilin‐1), and FA transport proteins 3 and 4, to suppress endothelial FA uptake, whereas PEDF deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation. Conclusions Decreasing expression of PEDF aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial FA uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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