Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits

This study analyzed the antiatherogenic effects of newly developed apolipoprotein A-I (ApoA-I) mimetic peptide/phospholipid complexes (ETC-642) against the aortic plaque burden in vivo. We used human macrophage cells to analyze cholesterol efflux by ETC-642. Watanabe-heritable hyperlipidemic (WHHL) rabbits were divided into 3 groups: low- (15 mg/kg) and high-dose ETC-642 (50 mg/kg), and placebo. The test material was injected twice/week for 12 weeks. The aortic plaque burden was assessed by intravascular ultrasound (IVUS) at 0 and 12 weeks. Plasma lipid profiles were analyzed by capillary isotachophoresis every 4 weeks. ETC-642 had an effect on cholesterol efflux comparable to that of conventional rHDL. In WHHL rabbits, high-dose ETC-642 inhibited the progression of aortic atherosclerosis compared to placebo. There was no change in the percentage of plaque volume (%PV) in the high-dose group between before (30.9%) and after infusion (28.6%), whereas there was a significant increase in the control group from 27.8% to 37.9%. ETC-642 significantly reduced charge-modified low-density lipoprotein (LDL) by converting more negative-charged modified LDL to less negative-charged LDL, and reduced small dense (sd) LDL by converting it into large, buoyant (lb) LDL. Changes in the %PV were positively correlated with changes in negative-charged modified LDL (r = 0.61, p < 0.01) and sdLDL (r = 0.59, p < 0.01), and negatively correlated with changes in less negative-charged LDL (r = −0.43, p < 0.01) and lbLDL (r = −0.57, p < 0.01). In conclusion, the ETC-642-induced remodeling of sdLDL to large and lbLDL and the enhancement of cholesterol efflux may prevent progression of the aortic plaque burden. HDL-based therapy may be useful for preventing the progression of plaque volume.

► We analyzed the antiatherogenic effects of ETC-642 against the plaque burden. ► ETC-642 inhibited the progression of aortic atherosclerosis. ► ETC-642 remodeled small dense LDL to large and buoyant LDL. ► HDL-based therapy may be useful for preventing the progression of plaque volume.