Introduction and objectives: A large number of epidemiological studies have found that serum High-density lipoprotein cholesterol (HDL-C) level is inversely associated with the risk of atherosclerosis. HDL-C can delay the occurrence and development of atherosclerosis, and the mechanism is mainly through promoting reverse cholesterol transport (RCT). ATP-binding cassette transporter A1 (ABCA1) is a transporter that mediates cholesterol reversal and thus beneficial for preventing atherosclerosis. In the previous study, we have found natural compound rutaecarpine (RUT) had anti-atherosclerotic effect in ApoE-deficient (ApoE-/-) mice through regulating ABCA1 activity. In the present study, a series of compounds based on the optimization of RUT were designed with the aim of improving the ABCA1 up-regulatory activity and anti-atherosclerotic efficacy.
Methods and results: Using an ABCA1p-LUC HepG2 model, R3 was identified to have better ABCA1 activity than RUT. Western blot and real time qPCR assay showed that R3 could upregulate the mRNA and protein levels of ABCA1in HepG2 and RAW264.7 cells. R3 could also upregulate other RCT receptors including SR-BI/CLA-1 and ABCG1 expression but not affect FAS, SREBP-1c and CD36 expression. Foam cell assay showed that R3 could inhibit lipids accumulation in RAW264.7 cell. Cholesterol efflux assay showed that R3 could induce HDL-mediated cholesterol efflux in RAW264.7 through ABCA1. In vivo studies showed that R3 significantly reduced serum TC, TG, LDL-C levels and increased HDL-C level in both hyperlipaemia golden hamster model and high fat diet induced atherosclerotic ApoE–/– mice model. Meanwhile, R3 treatment decreased liver lipid and cholesterol constants and increased liver RCT related genes’ expression in both mice models. Importantly, R3 treatment significantly reduced en face aorta atherosclerotic lesions in ApoE–/– mice.
Conclusions: Our data indicated that R3 was an effective molecule in regulating lipid and cholesterol metabolism and it might be used as a promising therapeutic agent for treating atherosclerosis in the future.