1. Statins Combined with AAV8-TBG-LOX-1 Reduce the Vascular Lipid-driven Inflammatory Response and Inhibit Atherosclerosis.
- Author
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Zhou WP, Fan XR, Li SH, Zeng ZL, and Wei YM
- Subjects
- Animals, Mice, Humans, Hepatocytes metabolism, Hepatocytes drug effects, Liver metabolism, Lipid Metabolism drug effects, Apolipoproteins E genetics, Apolipoproteins E metabolism, Inflammation metabolism, Inflammation genetics, Mice, Knockout, Mice, Inbred C57BL, Male, Disease Models, Animal, Atherosclerosis metabolism, Atherosclerosis genetics, Atherosclerosis drug therapy, Dependovirus genetics, Scavenger Receptors, Class E metabolism, Scavenger Receptors, Class E genetics, Lipoproteins, LDL metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
- Abstract
Objective: Imbalances in liver lipid metabolism and inflammatory reactions driven by oxidized lipid deposition in blood vessels constitute the core of atherosclerosis. Insufficient degradation of cholesterol in the liver promotes oxidative modification of lipid particles and their deposition on the blood vessel wall in the peripheral circulation. The blood vessel wall engulfs and processes oxidized low-density lipoprotein (Ox-LDL) as foreign matter through pattern recognition receptors, ultimately forming lipid-encapsulated plaques. Among them, endothelial cell oxidized low density lipoprotein receptor 1 (LOX1) phagocytosis is an important link in initiating and promoting this mechanism, and hepatocytes, which are the core of lipid metabolism, are unable to process oxidized lipid particles because of the lack of receptors for the uptake of Ox-LDL. The objective of this study was to investigate whether continuous clearance of Ox-LDL through the liver metabolic pathway could provide better protection against statins therapy., Methods: This study used statins combined with an adeno-associated virus (AAV8-TBG-LOX-1) liver-specific transfection system developed by our research group, in which statins reduced the level of LDL and promoted the ectopic expression of LOX-1 in hepatocytes to clear the continuous production of Ox-LDL. An ApoE knockout mouse model was used to study the effects of virus transfection and liver uptake and degradation of Ox-LDL. Laser confocal detection, Oil red staining and immunofluorescence staining were used to observe the effects of combined therapy on anti-atherosclerotic lesions., Results: Laser confocal microscopy revealed that the recombinant viral vector AAV8-TBG-LOX-1 could specifically transfect hepatocytes and express LOX-1, which mediate hepatocyte phagocytosis and clearance of Ox-LDL. Oil red O staining of the aorta and valvular ring suggested that statins combined with AAV8-TBG-LOX-1 significantly inhibited atherosclerotic lesions. Tissue immunofluorescence staining suggested that statins could reduce the aggregation of macrophages in plaques and that combined therapy could further reduce the aggregation of macrophages in plaques., Conclusion: Statins combined with AAV8-TBG-LOX-1 can alleviate the inflammatory response driven by lipids in the vascular wall, reduce the deposition of macrophages in plaques and inhibit atherosclerosis., Competing Interests: Conflict of Interest Statement. The authors declare that they have no conflicts of interest., (© 2024. Huazhong University of Science and Technology.)
- Published
- 2024
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