Atorvastatin Enhances Foam Cell Lipophagy and Promotes Cholesterol Efflux Through the AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Abstract

Foam cells are the main pathological components of atherosclerosis. Therapies reducing foam cell formation can effectively prevent atherosclerotic diseases and cardiovascular events. Beyond lowering plasma cholesterol levels, the pleiotropic functions of statins in atherosclerosis have not been fully elucidated. In the present study, atorvastatin reduced cholesterol content and increased cholesterol efflux from foam cells in a concentration-dependent manner. Atorvastatin (10 μM) inhibited foam cell formation within 48 hours. Furthermore, we found that atorvastatin inhibited foam cell formation by promoting lipophagy, which was manifested by increased autophagy-related gene 5 (Atg5) expression, elevated ratio of microtubule-associated protein1 light chain 3 (LC3) II to LC3I, reduced p62 expression, and increased LC3 and lipid droplets colocalization in foam cells treated with atorvastatin. The autophagy inducer, rapamycin (Rap), did not increase the lipophagy enhancement effect of atorvastatin, but the autophagy inhibitor, 3-methyladenine, suppressed the effect of atorvastatin on Atg5 expression and the LC3II/LC3I ratio, as well as the increased p62 expression, suppressed lipophagy, attenuated cholesterol efflux and increased cholesterol content in foam cells. Further analysis revealed that atorvastatin promoted lipophagy by upregulating adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation, and downregulating mammalian target of rapamycin phosphorylation, whereas the AMPK inhibiter, compound C, attenuated these effects. In conclusion, atorvastatin reduced lipid accumulation and promoted cholesterol efflux by enhancing lipophagy in foam cells and thereby inhibited foam cell formation. The enhanced lipophagy of foam cells was exerted through the AMPK/mammalian target of rapamycin signaling pathway.

Developing a Biomimetic 3D Neointimal Layer as a Prothrombotic Substrate for a Humanized In Vitro Model of Atherothrombosis

“…This may be related to atorvastatin’s ability to reduce the accumulation of lipids within the neointimal biomimetic hydrogels. This work is consistent with previous studies that have reported that statin can decrease the intracellular lipid contents by stimulating the cholesterol efflux from foam cells [ 71 , 72 ]. As uptake of oxLDL has been shown to induce multiple changes in the cellular phenotype of foam cells [ 73 ], further assessment of the impact of atorvastatin on these genetic and epigenetic responses will be required to assess how atorvastatin has an impact on the thrombogenic properties of the biomimetic hydrogels.…”

Detection of lipid efflux from foam cell models using a label-free infrared method

“…It was found that atorvastatin enhanced cholesterol efflux and decreased cholesterol content in a dose dependent manner. 17,18 These data suggest that atorvastatin is able to switch macrophages from a pro-inflammatory to an antiinflammatory phenotype, an observation supported by Cheng et al, 14 who noted that atorvastatin was able to modulate the Th1/Th2 response in patients with chronic heart failure through inhibition of Th1 cytokine production. 14 The evaluation of cholesterol efflux is commonly conducted using radioisotope labelled cholesterol that is loaded into cells and quantified.…”

High density lipoprotein as a therapeutic target: Focus on its functionality

“…Moreover, in a study carried out in vitro, rosuvastatin inhibited foam cell formation and stimulated ABCA1 and ABCG1 expression by promoting autophagy in macrophages (Zhang et al, 2021). Similarly, atorvastatin increased cholesterol efflux by promoting foam cell lipophagy (Zheng et al, 2021). Furthermore, pravastatin enhanced cholesterol efflux in chondrocytes (Wu et al, 2022).…”