Abstract
Atherosclerosis (AS) is a type of chronic vascular disease, and its etiology is not yet fully understood. AS is characterized by lipid deposition, atherosclerotic plaque formation, vascular stenosis or even complete blockage of the blood vessel wall. Clinical studies have shown that Danlou tablets (DLTs) can improve the heart function, quality of life, and prognosis of patients with coronary heart disease and myocardial infarction. However, its mechanism of action remains unknown. Our study revealed that DLTs ameliorated ApoE−/−AS mouse aortic atherosclerotic plaques [hematoxylin-eosin (HE) staining and small animal ultrasound] and reduced CD68+ macrophage infiltration, the expression of the inflammatory factor interferon-gamma (IFN-γ), vascular smooth muscle α-actin, and serum lipid levels. In vitro, in the macrophage foaming model, DLTs partially restored the activity of RAW264.7 cells, reduced the uptake of lipid droplets, and inhibited lipid droplet accumulation and apoptosis within BMDMs. We also found that Torin1, an autophagy agonist, reduced intracellular lipid deposition in BMDMs, as did DLTs. Moreover, DLTs upregulated the expression of the autophagy-related protein LC3II and decreased p62 accumulation in RAW264.7 cells. DLTs also inhibited the phosphorylation of p-PI3K, p-Akt, and p-mTOR, leading to upregulated autophagy in RAW264.7 cells. In summary, our results suggested that DLTs can promote autophagy in macrophages by inhibiting the PI3K/Akt/mTOR signaling pathway, thereby reducing foam cell formation and improving atherosclerosis.
Highlights
Atherosclerosis is a progressive disease characterized by the accumulation of lipid-rich macrophages on the inner wall of the artery, accompanied by the proliferation of vascular smooth muscle cells and fibrous matrix, forming asymmetric focal thickening of the intima, and gradually developing into the formation of atherosclerotic plaques
The results revealed middle- and high-dose Danlou tablets (DLTs) and atorvastatin reduced the number of atherosclerotic plaques compared with the model group (p < 0.01), whereas there is no significant difference between the low-dose DLT group and the model group in the number of plaques (p > 0.05)
The component-target network indicated that five target genes-GSK3b, ATG1, ATG5, PI3K and mTOR in autophagy pathways were closely associated with 253 active components of DLTs after molecular docking (Table 2)
Summary
Atherosclerosis is a progressive disease characterized by the accumulation of lipid-rich macrophages on the inner wall of the artery, accompanied by the proliferation of vascular smooth muscle cells and fibrous matrix, forming asymmetric focal thickening of the intima, and gradually developing into the formation of atherosclerotic plaques. Arterial plaque can cause vascular stenosis or even complete blockage and cause ischemia or infarction of the corresponding organ. The treatments of atherosclerosis mainly depend on statins, antithrombotic drugs and surgical intervention. Statins are currently the most effective drugs to prevent and treat cardiovascular events (Horodinschi, Stanescu et al, 2019). High-dose statin administration has been associated with severe side effects, including an increased risk of new-onset diabetes, liver damage, rhabdomyolysis, etc
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