The LOX-1 receptor ectopically expressed in the liver alleviates atherosclerosis by clearing Ox-LDL from the circulation

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 28; no. 1; pp. 26 - 15
• Main Authors: Wang, Zhiwen, Chen, Juan, Zeng, Zhuanglin, Zhang, Qing, Du, Gaohui, Guo, Xiaopeng, Wei, Yumiao
• Format: Journal Article
• Language: English
• Published: England BioMed Central 02.03.2022; BMC
• Subjects: AAV8; Animals; Atherosclerosis; Atherosclerosis - metabolism; Cardiovascular disease; Cholesterol; Endothelial Cells - metabolism; Glycoproteins; Intervention; Lipids; Lipoproteins, LDL - metabolism; Liver; Liver - metabolism; Low density lipoprotein; LOX-1; Metabolism; Mice; Ox-LDL; Oxidation; Physiology; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Vascular Cell Adhesion Molecule-1 - metabolism; Veins & arteries; AAV8; LOX-1; Liver; Atherosclerosis; Ox-LDL
• ISSN: 1076-1551; 1528-3658; 1528-3658
• DOI: 10.1186/s10020-022-00450-3

Oxidized Low-Density-Lipoprotein (Ox-LDL) is the core factor in the development of atherosclerosis. However, there are few therapies aimed at eliminating Ox-LDL. Here in this study, we investigate whether the ectopically expression of the lectin-like oxidized low density lipoprotein receptor (LOX-1) in the liver could lead to the elimination of circulating Ox-LDL and prevent the deposition in the vascular wall, thereby alleviating the progression of atherosclerosis. Apolipoprotein E-deficient (ApoE ) mice were randomly divided into three groups, the control group, the AAV8-TBG-eGFP group (eGFP group) and AAV8-TBG-LOX-1 group (LOX-1 group). In the LOX-1 group, mice received an injection of virus dilution AAV8-TBG-LOX-1 (1.16 × 10 virus genome (v.g)/animal/100 μl). The mice in the control group and eGFP group received the same amount of sterile saline and AAV8-TBG-eGFP virus dilution injections. The expression of LOX-1 in the liver was detected by immunofluorescent, western blot and immunohistochemistry. The safety of the virus was assessed by hematoxylin-eosin (H&E) staining, blood biochemical analyses and immunofluorescent. The function of LOX-1 in the liver was detected by the co-localization of LOX-1 and Dil-labeled Ox-LDL (Dil-Ox-LDL) under laser scanning confocal microscope. The extent of Ox-LDL in plasma was detected by ELISA. Changes in blood lipids were assessed through blood biochemical analysis. The progression of atherosclerotic lesions was detected by Oil red O staining. And the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) in endothelial cells and the extent and migration of macrophages in atherosclerotic plaque were detected by immunofluorescence staining. The protein expression in liver was assessed by qRT-PCR and western blot. The expression of LOX-1 was stable in liver within 4 weeks. Ectopically expressed LOX-1 in the liver phagocytosed and degraded Ox-LDL and reduced Ox-LDL from circulation but did not have a significant effect on blood lipid levels. After the expression of LOX-1 in liver, Ox-LDL can be cleared by the hepatocytes, thereby reducing VCAM-1 expression in vascular endothelium and the migration of macrophages in plaques, and eventually alleviating the progression of atherosclerosis. Functional expression of LOX-1 in hepatocytes may facilitate the metabolic clearance of Ox-LDL by upregulating the expression of ATP-binding cassette G5 and G8 (ABCG5/G8), which is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Ectopic liver-specific expression of LOX-1 receptor alleviates the progression of atherosclerosis by clearing Ox-LDL from circulation.