Abstract 10759: Sustained Effects of Apolipoprotein E Mimetic Peptides on Established Atherosclerotic Lesions in Apo E Null Mice
Background: Apolipoprotein E (apoE) has been shown to have direct effects on the artery wall that promote regression of atherosclerosis and improve vascular function. The dual domain apoE mimetic peptide Ac-hE18A-NH2 (AEM-28) and single domain peptide mR18L reduce plasma cholesterol levels and reduce atherosclerosis in dyslipidemic animal models. The purpose of this study was to examine the effects of Apo E mimetic peptides on atherosclerotic lesions after cessation of treatment.
Methods: Female apoE null mice (14 weeks old, n=39) were fed Western diet for 6 weeks.. This raised their cholesterol levels to 1373±129 mg/dl. They were then changed to normal chow for two weeks. and randomized into three groups. Two groups of animals (13 in each group) received AEM-28 or mR18L,(100μg/100μl of saline), retro-orbitally three times a week for four weeks, The control group received an equal volume of saline. All animals were then continued on a chow diet for an additional four weeks without any treatment.
Results: At the end of the treatment period, both of the peptides had reduced plasma cholesterol levels significantly (357±57 mg/dl, and 444±75 mg/dl, respectively, for AEM-28 and mR18L p<0.001 and 0.002, respectively vs saline), compared to control (536±77 mg/dl; four weeks post peptide treatment cholesterol levels in all groups were similar (479±70 mg/dl). En face lesion analysis showed that AEM-28 treated animals had 41% less lesion compared to control (9.4±2.4 % vs 15.8+3.6%; p<0.001), while the mR18L treated animals had 17% less lesion (13.1 ± 4.4 % p=0.067 vs saline). AEM-28 treated animals also had a 32% decrease in aortic sinus lesions at termination (p<0.02.. At the end of treatment, plasma from both peptide groups showed enhanced PON-1 activity. However, only the AEM-28 group had enhanced PON-1 activity at termination.
Conclusion: This investigation represents the first report of a short-term treatment that results in a sustained reduction in aortic atherosclerotic lesions. The mechanism by which AEM-28 confers this sustained effect on the artery wall remains to be fully elucidated. A therapeutic that rapidly reduces atheroma burden and stabilizes cholesterol laden lesions could represent an important advance in the treatment of cardiovascular disease.
- © 2013 by American Heart Association, Inc.