OBJECTIVE  To mitigate excessive cholesterol accumulation in atherosclerosis(AS) plaques, sphingomyelin (SM) with high cholesterol affinity is introduced on the substrate of the nascent discoidal high-density lipoprotein (pre-βHDL) to construct the HDL analog SM/βHDL. To investigate SM/βHDL's cholesterol reverse transport influence and anti-AS therapeutic potential.

METHODS  Firstly, SM/βHDL was prepared by thin film dispersion method and characterized. Its cholesterol reversal efficiency was examined using an in vitro cell model simulating AS plaque and liver metabolism. ApoE^−/− male mice combined with high cholesterol and fat diet were used to establish AS model. The therapeutic effect of SM/βHDL on AS plaque elimination was investigated by serum lipid detection, oil red O staining and section staining, respectively.

RESULTS  SM/βHDL diameter was (23.42±1.46)nm, exhibiting discoid morphologies. Compared with βHDL without introducing SM, SM/βHDL had a higher cholesterol affinity with an affinity KD value of 423 nmol·L⁻¹. SM/βHDL enhanced the cholesterol reversal efficiency by (9.88±0.66)%, a 27.5% rise compared to βHDL, and a 56.6% increased over the clinical phase III HDL product CSL-112. The findings indicated that SM/βHDL primarily targeted the lesion site, leading to a significant improvement in serum lipid composition, a reduction in AS plaque area, and a decrease in the number of macrophages and vascular smooth muscle cells, thereby enhancing plaque stability.

CONCLUSION  This research proposes a cholesterol efflux-enhancing SM/βHDL, which effectively reverses and attenuates AS plaques, thus providing a novel and promising therapeutic strategy for treating AS with βHDL.