Two apolipoprotein E mimetic peptides with similar cholesterol reducing properties exhibit differential atheroprotective effects in LDL-R null mice.

Abstract

OBJECTIVE:

We investigated two apoE mimetic peptides with similar long-term plasma cholesterol reducing abilities for their effects on atherosclerotic lesions in Western diet-fed female LDL-receptor (LDL-R) null mice.

METHODS AND RESULTS:

Single doses of peptides Ac-hE18A-NH(2) and mR18L were administered retro-orbitally to LDL-R null mice on Western diet and plasma cholesterol was measured at 10 min, 4 h, and 24 h post administration. Peptide mR18L and not Ac-hE18A-NH(2) reduced plasma cholesterol levels significantly at 4 h post administration. However, multiple administrations (100 μg/mouse twice weekly for 8 weeks) resulted in a similar reduction in plasma cholesterol. Only the plasma from the Ac-hE18A-NH(2) group had significantly reduced reactive oxygen species levels at the end of the treatment protocol. Both mR18L and Ac-hE18A-NH(2) showed reduced atherosclerotic lesion areas. However, peptide Ac-hE18A-NH(2) was significantly more effective in inhibiting atherosclerosis. Both peptides reduced total plaque macrophage load compared to the saline treated animals, with peptide Ac-hE18A-NH(2) having a greater reduction. Incubation of HepG2 cells and THP-1 monocyte-derived macrophages with both peptides in the presence of oxidized phospholipid showed that Ac-hE18A-NH(2) promotes the secretion of apoE from the cells whereas mR18L does not.

CONCLUSIONS:

Despite similar reductions in plasma cholesterol levels, Ac-hE18A-NH(2) was more effective in inhibiting lesions than mR18L, possibly due to its ability to promote the secretion of apoE from hepatocytes and macrophages.

• Authors: Shaila P Handattu, Gaurav Nayyar, David W Garber, Mayakonda N Palgunachari, Candyce E Monroe, Tamara D Keenum, Vinod K Mishra, Geeta Datta, G M Anantharamaiah
• Journal: Atherosclerosis (Atherosclerosis) Vol. 227 Issue 1 Pg. 58-64 (Mar 2013) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 23159231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Ac-hE18A-NH(2)
• Apolipoproteins E
• Lipoproteins
• Peptide Fragments
• Peptides
• Reactive Oxygen Species
• Receptors, LDL
• mR18L peptide
• Cholesterol

Topics

• Animals
• Apolipoproteins E (chemistry, metabolism)
• Atherosclerosis (prevention & control)
• Cholesterol (blood)
• Female
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Lipoproteins (pharmacology)
• Macrophages (drug effects, metabolism)
• Mice
• Peptide Fragments (pharmacology)
• Peptides (pharmacology)
• Reactive Oxygen Species (blood)
• Receptors, LDL (genetics)