Promoting reverse cholesterol transport contributes to the amelioration of atherosclerosis by paeoniflorin

Reverse cholesterol transport (RCT) offers a practical approach to mitigating atherosclerosis. Paeoniflorin, a monoterpenoid glycoside found in plants of the Paeoniaceae family, has shown various effects on cardiovascular and liver diseases. Nevertheless, its impact on atherosclerosis in vivo remains poorly understood. The objective of this study is to examine the effect of paeoniflorin on atherosclerosis using apolipoprotein E-deficient (ApoE^-/-) mice and explore the underlying mechanisms, with a specific focus on its modulation of RCT. ApoE^-/- mice were continuously administered paeoniflorin by gavage for three months. We assessed lipid parameters in serum and examined pathological changes and gene expressions related to RCT pathways in the aorta, liver, and intestine. In an in vitro study, we utilized RAW264.7 macrophages to investigate the inhibitory effect of paeoniflorin on foam cell formation and its potential to promote RCT. The results revealed that paeoniflorin reduced atherosclerosis, alleviated hyperlipidemia, and mitigated hepatic steatosis. Paeoniflorin may promote RCT by stimulating cholesterol efflux from macrophages via the liver X receptor alpha pathway, enhancing serum high-density lipoprotein cholesterol and apolipoprotein A-I levels, and regulating key genes in hepatic and intestinal RCT. Additionally, treatment ApoE^-/- mice with paeoniflorin suppressed the expression of inflammation-related genes, including CD68, tumor necrosis factor alpha, and monocyte chemoattractant protein-1, and mitigated oxidative stress in both the aorta and liver. Our results indicated that paeoniflorin has the potential to be a more effective and safer treatment for atherosclerosis, thanks to its promotion of RCT and its anti-inflammatory and anti-oxidative effects.