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Floralozone attenuates atherosclerotic vascular injury by regulating AMPKα/SREBP-1c pathway and down-regulating
Ya-Qi Guo1,2, Hong-Lin Zhao2, Jin-Ming Zhao2
1College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, China.
Background:
Severe disruption of lipid metabolism in vivo is one of the central mechanisms in the development of atherosclerotic vascular injury (AVI). Reverse cholesterol transport (RCT) plays a pivotal role in eliminating excess cholesterol, preventing lipid deposition in the aorta, and reducing plaque formation associated with AVI. Floralozone (FL) reduces endothelial cell injury in AVI rats by regulating sphingosine-1-phosphate (S1P) expression. However, FL's potential to prevent AVI by modulating cholesterol metabolism remains unknown.
Methods:
In this study, network pharmacology and molecular docking predicted FL's potential targets in AVI protection. AVI rats were induced with a high-sugar, high-fat diet and vitamin D3 injection. FL intervention's effects on aortic pathology and lipid levels were assessed. The expression levels of SREBP-1c, PPARγ, ABCA1, and ABCG1 were evaluated. Raw264.7 macrophages were induced to form foam cells with ox-LDL, and FL's effects on the AMPKα/SREBP-1c pathway and miR-33-5p were investigated.
Results:
FL reduced lipid levels and SREBP-1c expression, increased HDL-C, promoted ABCA1- and ABCG1-mediated cholesterol efflux, and reduced aortic cholesterol accumulation. The AMPKα inhibitor dorsomorphin blocked FL's inhibition of intracellular cholesterol accumulation and SREBP1 down-regulation in foam cells. FL decreased miR-33-5p expression but up-regulated PPARγ, promoting ABCA1- and ABCG1-mediated cholesterol efflux. However, miR-33-5p mimic reduced FL-induced cholesterol efflux, while miR-33-5p inhibitor increased it.
Conclusion:
FL may promote foam cell cholesterol efflux by modifying the AMPKα/SREBP-1c pathway and down-regulating miR-33-5p, which targets cholesterol metabolism genes (PPARγ, ABCA1, and ABCG1). These findings provide a new insight into the protective effect of FL on AVI.
Insights
Floralozone (FL) enhances cholesterol efflux in atherosclerotic vascular injury (AVI) by modulating the AMPKα/SREBP-1c pathway and reducing miR-33-5p. This improves lipid metabolism and reduces aortic cholesterol accumulation, offering a new protective strategy for AVI.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Atherosclerotic vascular injury (AVI) involves severe lipid metabolism disruption.
- Reverse cholesterol transport (RCT) is crucial for preventing cholesterol deposition and plaque formation in AVI.
- Floralozone (FL) is known to reduce endothelial cell injury in AVI, but its role in cholesterol metabolism is unclear.
Purpose of the Study:
- To investigate the potential of Floralozone (FL) in preventing atherosclerotic vascular injury (AVI) by modulating cholesterol metabolism.
- To elucidate the molecular mechanisms underlying FL's effects on lipid metabolism and cholesterol transport in AVI.
Main Methods:
- Network pharmacology and molecular docking were used to predict FL's targets in AVI.
- AVI rat models were established, and FL's effects on aortic pathology and lipid profiles were assessed.
- Key genes and microRNAs involved in cholesterol metabolism (SREBP-1c, PPARγ, ABCA1, ABCG1, miR-33-5p) were analyzed in vivo and in vitro using foam cell models.
Main Results:
- FL treatment reduced lipid levels, SREBP-1c expression, and aortic cholesterol accumulation while increasing HDL-C.
- FL promoted ABCA1 and ABCG1 expression and cholesterol efflux, partly via the AMPKα/SREBP-1c pathway.
- FL decreased miR-33-5p expression, which in turn up-regulated PPARγ, ABCA1, and ABCG1, enhancing cholesterol efflux.
Conclusions:
- Floralozone (FL) promotes cholesterol efflux from foam cells by modulating the AMPKα/SREBP-1c pathway and down-regulating miR-33-5p.
- FL's action on miR-33-5p influences key cholesterol metabolism genes (PPARγ, ABCA1, ABCG1), offering a novel therapeutic insight for AVI.
