Danlou Tablets Inhibit Atherosclerosis in Apolipoprotein E-Deficient Mice by Inducing Macrophage Autophagy: The Role of the PI3K-Akt-mTOR Pathway

Liu, Chunping; Chen, Guiling; Chen, Yanfen; Dang, Yue; Nie, Guangning; Wu, Dinghong; Li, Jinhua; Chen, Zide; Yang, Hailong; He, Dongyue; Xiong, Lize; Sun, Jingbo; Lu, Jiahong; Wang, Lei

doi:10.3389/fphar.2021.724670

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…The PI3K/AKT/mTOR signaling pathway is a classical autophagic pathway. Meanwhile, it was also found that Danlou tablets (DLTs) can promote autophagy in macrophage by inhibiting this signaling pathway, thereby reducing FCs formation and improving AS ( Liu et al, 2021 ). Despite lots of studies on the role of autophagy in anti-AS, those on the specific mechanism of autophagy is limited.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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Background Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. Methods The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Results Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Conclusion Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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“…68,69 However, there are currently no available data showing its effect on the inhibition of atherosclerosis progression. 70 Moreover, Torin1 inhibits mTORC2, which is involved in insulin signaling. Thus, long-term drug use of the drug has serious adverse effects, such as insulin resistance and glucose intolerance.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages

Qu,

Zhou,

Jiang

et al. 2023

ATVB

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BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid–mTORC1–autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS: We observed that Gpr137b-ps was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE −/− mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow–derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid–mTORC1–autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps–regulated autophagy. RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid–induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (GTPase-activating protein-binding protein), which tethers the TSC complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid–mTORC1–autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.

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“…In conclusion, macrophages promote and maintain inflammatory response and promote the development of AS in patients with psoriasis. In addition, macrophages not only promote the expression of inflammatory factors in patients with psoriasis, but also increase the formation of cholesterol crystals and lipid uptake, affect cholesterol excretion, and further promote the occurrence of AS ( 45 , 48 , 49 ).…”

Section: Immunity and Psoriasis - Atherosclerosis Are Closely Relatedmentioning

confidence: 99%

Immunity: Psoriasis comorbid with atherosclerosis

Liu

Chen²,

Liu³

et al. 2022

Front. Immunol.

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Psoriasis is an immune-mediated, persistent inflammatory disease with a genetic predisposition, and the involvement of multiple organs in psoriasis remains indicative of systemic disease. Atherosclerosis (AS) is a common complication of patients with severe or prolonged psoriasis. The specific pathogenesis of psoriasis is still unclear. Current studies suggest that psoriasis is a polygenic genetic disease with the interaction of multiple factors such as heredity and environment. Keratinocytes are proliferated through immune-mediated inflammatory pathway, which leads to cell activation, infiltration of dermis cells and release of inflammatory factors. Activation of inflammatory cells and pro-inflammatory factors play an important role in the progression of psoriasis and atherosclerosis. Studies have found that there is a close relationship between psoriasis and atherosclerosis, and systemic inflammation may be the common feature of psoriasis and AS. This paper attempts to explore the possibility of the relationship between psoriasis and atherosclerotic comorbidities from the aspects of potential epidemiology and immune mechanism, in order to provide some reference for the subsequent scientific research.

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Danlou Tablets Inhibit Atherosclerosis in Apolipoprotein E-Deficient Mice by Inducing Macrophage Autophagy: The Role of the PI3K-Akt-mTOR Pathway

Cited by 11 publications

References 32 publications

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages

Immunity: Psoriasis comorbid with atherosclerosis

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