Two adjacent domains (141-150 and 151-160) of apoE covalently linked to a class A amphipathic helical peptide exhibit opposite atherogenic effects.

Academic Article

Abstract

  • OBJECTIVE: We recently described anti-atherogenic properties of the dual domain peptide Ac-hE18A-NH(2) derived by covalently linking the heparin binding domain 141-150 of apoE to 18A, a class A amphipathic helical peptide. In this paper we have compared the properties of Ac-hE18A-NH(2) with the non-heparin binding 151-160 region of apoE linked to 18A (Ac-nhE18A-NH(2)). METHODS AND RESULTS: Both peptides were highly helical in solution and in association with lipids. Ac-hE18A-NH(2) and not Ac-nhE18A-NH(2) enhanced uptake of low density lipoprotein (LDL) in HepG2 cells. While Ac-hE18A-NH(2) retarded the electrophoretic mobility of LDL, Ac-nhE18A-NH(2) slightly enhanced mobility. Ac-hE18A-NH(2) reduced monocyte association with endothelial cells, while Ac-nhE18A-NH(2) increased it. Ac-hE18A-NH(2) also reduced lipid hydroperoxide content of LDL while Ac-nhE18A-NH(2) increased it. A single administration of Ac-hE18A-NH(2) (100 μg/mouse) into apoE null mice dramatically reduced cholesterol (from 600 mg/dL to 180 mg/dL at 5 min and to 60 mg/dL at 5h) while Ac-nhE18A-NH(2) had no effect. Administration (100 μg/mouse/day, three days a week) into apoE null mice for six weeks showed Ac-hE18A-NH(2) group having a moderate aortic sinus lesion reduction compared with the control group (-15.1%), while the Ac-nhE18A-NH(2) administered group had increased lesion area (+33.0% vs controls and 36.1% vs Ac-hE18A-NH(2)). Plasma from mice administered Ac-hE18A-NH(2) for six weeks showed a significant reduction in plasma cholesterol and triglyceride levels and increase in paraoxonase-1 (PON-1) activity compared to controls, while Ac-nhE18A-NH(2) caused no change in plasma cholesterol and decreased PON-1 activity. CONCLUSION: It is proposed that Ac-hE18A-NH(2) reduced lesion progression in apoE null mice due to its anti-inflammatory and lipoprotein clearing properties, while Ac-nhE18A-NH(2) exhibited pro-atherogenic effects.
  • Published In

  • Atherosclerosis  Journal
  • Keywords

  • Animals, Apolipoproteins E, Aryldialkylphosphatase, Atherosclerosis, Cholesterol, Endothelial Cells, Female, Hep G2 Cells, Heparan Sulfate Proteoglycans, Humans, Lipoproteins, Lipoproteins, LDL, Mice, Monocytes, Peptide Fragments, Protein Structure, Secondary, Protein Structure, Tertiary, Triglycerides
  • Digital Object Identifier (doi)

    Pubmed Id

  • 3157345
  • Authorlist

  • Nayyar G; Handattu SP; Monroe CE; Chaddha M; Datta G; Mishra VK; Keenum TD; Palgunachari MN; Garber DW; Anantharamaiah GM
  • Start Page

  • 449
  • End Page

  • 457
  • Volume

  • 213
  • Issue

  • 2