Experimental Study On Antiatherosclerosis With EL Antisense

Objective:Plasma high-density lipoprotein (HDL) concentrations are inversely correlated with atherosclerosis. Endothelial lipase (EL) is an important enzyme that mediates HDL metabolism by hydrolyzing phospholipids. In the current study, we examined effects of EL antisense oligonucleotides (ASO) on HDL metabolism in rabbits.Methods:The rabbits were intravenously injected with EL ASO (40mg/kg) for 6 weeks and compared with rabbits injected with mismatched controls (n=8, for each group). Plasma total cholesterol, triglycerides and HDL-cholesterol were measured weekly and lipoproteins were analyzed at the end of experiment. After 6 weeks of ASO treatment, compared with the control group, there was no apparent changes in HDL levels between two groups. We also examined the expression of EL mRNA in liver and adrenal glands by real-time RT-PCR, the main target of EL ASO. The EL mRNA expression levels were decreased by 50% in EL ASO treated group compared to the controls. Furthermore, ultracentrifugation analysis revealed that the large-size HDL levels were increased, although there was no significant differerce in HDL-cholesterol levels in EL ASO treated group.The diameter of 15nm,13.5nm,12.1nm was obviously increased compare with the control group,especially the diameter of 12.1nm ,the difference was significant (P<0.01).Results:The inhibition of EL expression by ASO leads to modulation of the HDL particle size even though without altering the plasma levels of HDL. Larger particles increased markedly,as we konw,the larger particles are more effective than the small particles with carrying cholesterol,and it play important role in reverse cholesterol transport. These results suggest that EL has important effects on the HDL metabolism,it induced antiatherosclerosis by modulating the HDL particle size.