title: 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.
  
  
  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.affiliation: Department of Medicine and Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Shaila P
authors.initials: SP
authors.lastname: Handattu
authors.forename: Gaurav
authors.initials: G
authors.lastname: Nayyar
authors.forename: David W
authors.initials: DW
authors.lastname: Garber
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.forename: Candyce E
authors.initials: CE
authors.lastname: Monroe
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Keenum
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000097:blood; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: C478448:Ac-hE18A-NH(2); D001057:Apolipoproteins E; D008074:Lipoproteins; D010446:Peptide Fragments; D010455:Peptides; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; C582615:mR18L peptide; D002784:Cholesterol