Statins Combined with AAV8-TBG-LOX-1 Reduce the Vascular Lipid-driven Inflammatory Response and Inhibit Atherosclerosis

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外文摘要：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.

外文关键词：

atherosclerosisoxidized low-density lipoproteinstatinadeno-associated virusAAV8-TBG-LOX-1

作者：

Wen-ping ZHOU、Xin-rui FAN、Song-hai LI、Zhuang-lin ZENG、Yu-miao WEI

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作者单位：

Department of Cardiology,The Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430014,China

Key Laboratory for Molecular Diagnosis of Hubei Province,The Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430014,China

Sleep and Neuro Imaging Center,Faculty of Psychology,Southwest University,Chongqing 400715,China

Department of Cardiology,Wuhan Fourth Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430033,China

Department of Emergency Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

Department of Cardiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

Hubei Key Laboratory of Biological Targeted Therapy,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

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出版年：

2024

DOI：

10.1007/s11596-024-2954-3

当代医学科学(英文)

华中科技大学同济医学院

当代医学科学(英文)

影响因子：0.748

ISSN：2096-5230

年,卷(期)：2024.44(6)