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

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• 作者：Shaila P. Handattu¹ ; Gaurav Nayyar¹ ; David W. Garber ; ^{Dgarber@uab.edu} ; Mayakonda N. Palgunachari ; Candyce E. Monroe ; Tamara D. Keenum ; Vinod K. Mishra ; Geeta Datta ; G.M. Anantharamaiah
• 关键词：Atherosclerosis ; Cholesterol ; Peptides ; Oxidation ; Inflammation
• 刊名：Atherosclerosis
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：227
• 期：1
• 页码：58-64
• 全文大小：637 K

文摘

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-NH₂ 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-NH₂ reduced plasma cholesterol levels significantly at 4?h post administration. However, multiple administrations (100?¦Ìg/mouse twice weekly for 8 weeks) resulted in a similar reduction in plasma cholesterol. Only the plasma from the Ac-hE18A-NH₂ group had significantly reduced reactive oxygen species levels at the end of the treatment protocol. Both mR18L and Ac-hE18A-NH₂ showed reduced atherosclerotic lesion areas. However, peptide Ac-hE18A-NH₂ was significantly more effective in inhibiting atherosclerosis. Both peptides reduced total plaque macrophage load compared to the saline treated animals, with peptide Ac-hE18A-NH₂ 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-NH₂ promotes the secretion of apoE from the cells whereas mR18L does not.

Conclusions

Despite similar reductions in plasma cholesterol levels, Ac-hE18A-NH₂ was more effective in inhibiting lesions than mR18L, possibly due to its ability to promote the secretion of apoE from hepatocytes and macrophages.