Construction and Its Efficacy Evaluation of Cholesterol-efflux Enhanced Discoidal High-density Lipoprotein for Anti-atherosclerosis
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.
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