Shen-Yuan-Dan Capsule Attenuates Atherosclerosis and Foam Cell Formation by Enhancing Autophagy and Inhibiting the PI3K/Akt/mTORC1 Signaling Pathway

Abstract

Background and Aim: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a crucial role in autophagy and inflammation. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic and anti-inflammatory effects in mice. However, its effects on autophagy and the PI3K/Akt/mTORC1 signaling pathway remain unclear. This study aimed to explore the effects of SYDC on autophagy and PI3K/Akt/mTORC1 signaling in the apolipoprotein E knockout (ApoE −/− ) mouse model and in macrophage-derived foam cells to delineate the underlying mechanism. Methods: After 6 weeks of high-fat diet, ApoE –/– mice were randomly grouped into control, Lipitor, low-SYDC (SYDC-L), middle-SYDC (SYDC-M), and high-SYDC (SYDC-H) groups (n = 10). The mice were intragastrically administered the respective treatment for 6 weeks. Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (80 µg/ml) for 24 h and then pretreated with SYDC freeze-dried powder for another 24 h. Cells treated with SYDC were co-cultured for 24 h with LY294002, tricirbine, and rapamycin to investigate the effects on the PI3K/Akt/mTORC1 signaling pathway. Results: SYDC ameliorated blood lipid levels, reduced the atherosclerotic index and plaque areas in the aortic root in mice, and inhibited total cholesterol (TC) levels and cholinesterase (ChE)/TC ratios in ox-LDL stimulated macrophages. Moreover, SYDC up-regulated Beclin1 and LC3II/I proteins in mice and in the ox-LDL–stimulated macrophages. Moreover, SYDC inhibited AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 in mice and in ox-LDL–stimulated macrophages. Furthermore, SYDC’s inhibitory of ChE/TC ratios in ox-LDL–stimulated macrophages was not changed by selective inhibition of the PI3K/Akt/mTORC1 pathway. Conclusions: Our results highlight that SYDC treatment attenuates foam cell formation by promoting autophagy via inhibiting activation of the PI3K/Akt/mTORC1 signaling pathway. This study provides new insights into the molecular mechanism underlying SYDC’s therapeutic potential for treating atherosclerosis.

MiR‐9 promotes angiogenesis of endothelial progenitor cell to facilitate thrombi recanalization via targeting TRPM7 through PI3K/Akt/autophagy pathway

“…It has been demonstrated that PI3K/Akt/autophagy pathway is closely related to the regulation of cells migration and angiogenesis . The results also indicated the down‐regulation and up‐regulation of PI3K and Akt phosphorylation were found in EPCs with miR‐9‐5p mimics and inhibitor, respectively (Figure 5).…”

Long non‐coding RNA HULC protects against atherosclerosis via inhibition of PI3K/AKT signaling pathway

“…There is a study identifying that inhibition of PI3K/AKT/ mammalian target of rapamycin complex 1 (mTORC1) signaling pathway activation partially ameliorates AS evidenced by reduced blood lipid levels and TC content. 21 Currently, up-regulated HULC is proved to ameliorate TNF-α-induced inflammatory injury in osteoarthritis. 18 Besides that, it is previously documented that PI3K/AKT inhibitor LY294002 reduces TNF-α and IL-6 levels in retinopathy.…”

“…Furthermore, the study has investigated that HULC lowers blood lipid levels and inhibits inflammatory and oxidative stress‐related factor expression via inactivating PI3K/AKT signaling pathway in AS mice. There is a study identifying that inhibition of PI3K/AKT/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway activation partially ameliorates AS evidenced by reduced blood lipid levels and TC content 21 . Currently, up‐regulated HULC is proved to ameliorate TNF‐α‐induced inflammatory injury in osteoarthritis 18 .…”

Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway

“…Atherosclerosis is the most common cause of ischaemic heart disease and stroke; it is closely associated with the occurrence of acute cardiovascular events, which have a huge impact on human life and health, accounting for 20% of total mortalities worldwide (1). It is widely known that during the early stages of atherosclerosis, monocytes enter the endothelial layer and differentiate into macrophages under the action of adhesion molecules and cytokines (2)(3)(4). For example, in one previous study, autopsies of patients with atherosclerosis discovered the accumulation of a large number of macrophages, lymphocytes and foam cells in the coronary artery plaques (2).…”

“…It is widely known that during the early stages of atherosclerosis, monocytes enter the endothelial layer and differentiate into macrophages under the action of adhesion molecules and cytokines (2)(3)(4). For example, in one previous study, autopsies of patients with atherosclerosis discovered the accumulation of a large number of macrophages, lymphocytes and foam cells in the coronary artery plaques (2). Macrophages are mainly divided into two different subtypes: M1-type macrophages are mainly found in unstable plaques, whereas M2-type macrophages are predominantly found in stable plaque tissue (5,6).…”