Abstract 13577: Both Apolipoprotein E Mimetic and Apolipoprotein A-I Mimetic Reduce Lesion Formation in Old Female Apolipoprotein E Knockout Mice.
Background. Apolipoprotein E (apoE) mimetic Ac-hE18A-NH2 was designed to enhance hepatic uptake of plasma apolipoprotein B containing lipoproteins by covalently linking the putative receptor binding domain 141-150 of apoE with the class A amphipathic helical peptide 18A. An analog of 18A called 4F is an apoA-I mimetic peptide that is capable of inhibiting atherosclerosis in apoE null mice without reducing plasma cholesterol, presumably via its anti-inflammatory properties. In these experiments, we have compared the effect of administration of both the apoA-I mimetic 4F and apoE mimetic Ac-hE18A-NH2 in 24 week old female apoE null mice with already existing lesions.
Methods and Results. 100μg/mouse/day of apoE mimetic was administered retro-orbitally three times a week for six weeks whereas 100 μg/mouse/day of 4F was administered intraperitoneally every day for six weeks. Age matched controls were injected with saline everyday for six weeks. At the end of six weeks compared to control plasma cholesterol levels (353.708+98.181 mg/dl) plasma cholesterol levels of Ac-hE18A-NH2 administered mice were significantly lower (262.750+78.543mg/dl); whereas 4F administration did not change cholesterol levels significantly (336.192+39.711mg/dl). However, both 4F and Ac-hE18A-NH2 showed reduced percent lesion area on enface lesion analysis to a similar extent (7.394+2.799, n= 12 p<0.001 vs control for 4F, and 6.352+3.674, n=12, p<0.001 vs control for Ac-hE18A-NH2) compared to the control group (14.701+5.385, n=12). Terminal plasma obtained from peptide administered mice showed reduction in lipid hydroperoxide in 4F treated animals compared to the plasma from control animals. Ac-hE18A-NH2 enhanced anti-oxidant enzyme paraoxonase-1 activity. In a separate experiment, only two times a week administration of apo E mimetic reduced lesion formation to the same extent as 4F daily administered.
Conclusions. While apoE mimetic reduced plasma cholesterol and inhibited progression of lesion, apoA-I mimetic reduced lesion progression to a similar extent without any change in plasma cholesterol levels via its ability to reduce plasma oxidized lipid levels.
- © 2011 by American Heart Association, Inc.