Danthron attenuates experimental atherosclerosis by targeting foam cell formation

Abstract

New findings: What is the central question of this study? Does danthron alleviate experimental atherosclerosis by inhibiting the formation of foam cells? What are the main findings and their importance? Danthron improved serum lipid profiles and significantly reduced the atherosclerotic plaque areas and lipid accumulation in the aortic root of ApoE^-/- mice. Danthron inhibited foam cell formation in oxidized low-density lipoprotein-induced RAW264.7 macrophages. Furthermore, danthron exerted its function in atherosclerosis at least partly through activating the AMP-activated protein kinase-sirtuin 1 signalling pathway. These findings suggest that danthron has the potential to alleviate atherosclerosis.

Abstract: Danthron, an ingredient isolated from Rheum palmatum L., has been revealed to reduce lipid accumulation in vitro. This study aimed to discover the effects of danthron on the development of atherosclerosis and to delineate the underlying mechanisms. For in vivo studies, male ApoE^-/- mice were fed a high-fat diet and orally treated with danthron (30 or 60 mg/kg/day) for 12 weeks. For in vitro studies, RAW264.7 cells were induced by oxidized low-density lipoprotein (ox-LDL, 50 μg/ml) for 48 h and subsequently administered danthron at appropriate concentrations for 24 h. AMP-activated protein kinase (AMPK) inhibitor compound C was added to ox-LDL-stimulated RAW264.7 cells 2 h before danthron administration to confirm the role of the AMPK signalling pathway in the regulation by danthron of foam cell formation. We found that danthron improved serum lipid profiles, and significantly reduced atherosclerotic plaque areas and lipid accumulation in the aortic root of atherosclerotic mice. Moreover, danthron upregulated the mRNA and protein expression of ATP-binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor α (LXRα), which play a crucial role in lipid metabolism, and activated the AMPK-sirtuin 1 (SIRT1) pathway. In an in vitro study, danthron inhibited foam cell formation in ox-LDL-induced RAW264.7 macrophages with an increase in the expression of ABCA1, ABCG1 and LXRα as well as activation of the AMPK-SIRT1 pathway. Furthermore, compound C abolished the effects of danthron on lipid accumulation and the protein expression of ABCA1/G1 and LXRα in vitro. Our results highlight that danthron possesses potential benefits in alleviating experimental atherosclerosis by targeting foam cell formation by activating the AMPK-SIRT1 signalling pathway.

Keywords: AMPK; SIRT1; atherosclerosis; danthron; foam cell.