title: Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits.
abstract: 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- (15mg/kg) and high-dose ETC-642 (50mg/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.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000378:metabolism*; D050197:Atherosclerosis / Q000473:pathology*; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics*; D057625:Isotachophoresis / Q000379:methods; D008077:Lipoproteins, LDL / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D010919:Placebos; D011817:Rabbits; D018084:Ultrasonography, Interventional / Q000379:methods
chemical_list: D016632:Apolipoprotein A-I; D008077:Lipoproteins, LDL; D010455:Peptides; D010919:Placebos; D002784:Cholesterol