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

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• 作者：Gaurav Nayyar ; Shaila P. H ; attu ; C ; yce E. Monroe ; Manjula Chaddha ; Geeta Datta ; Vinod K. Mishra ; Tamara D. Keenum ; Mayakonda N. Palgunachari ; David W. Garber ; G.M. Anantharamaiah
• 关键词：Atherosclerosis ; Lipid oxidation ; Apolipoproteins ; Cholesterol ; Peptides
• 刊名：Atherosclerosis
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：213
• 期：2
• 页码：449-457
• 全文大小：900 K

文摘

Objective

We recently described anti-atherogenic properties of the dual domain peptide Ac-hE18A-NH₂ 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-NH₂ with the non-heparin binding 151–160 region of apoE linked to 18A (Ac-nhE18A-NH₂).

Methods and results

Both peptides were highly helical in solution and in association with lipids. Ac-hE18A-NH₂ and not Ac-nhE18A-NH₂ enhanced uptake of low density lipoprotein (LDL) in HepG2 cells. While Ac-hE18A-NH₂ retarded the electrophoretic mobility of LDL, Ac-nhE18A-NH₂ slightly enhanced mobility. Ac-hE18A-NH₂ reduced monocyte association with endothelial cells, while Ac-nhE18A-NH₂ increased it. Ac-hE18A-NH₂ also reduced lipid hydroperoxide content of LDL while Ac-nhE18A-NH₂ increased it. A single administration of Ac-hE18A-NH₂ (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 5 h) while Ac-nhE18A-NH₂ had no effect. Administration (100 μg/mouse/day, three days a week) into apoE null mice for six weeks showed Ac-hE18A-NH₂ group having a moderate aortic sinus lesion reduction compared with the control group (−15.1 % ), while the Ac-nhE18A-NH₂ administered group had increased lesion area (+33.0 % vs controls and 36.1 % vs Ac-hE18A-NH₂). Plasma from mice administered Ac-hE18A-NH₂ 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-NH₂ caused no change in plasma cholesterol and decreased PON-1 activity.

Conclusion

It is proposed that Ac-hE18A-NH₂ reduced lesion progression in apoE null mice due to its anti-inflammatory and lipoprotein clearing properties, while Ac-nhE18A-NH₂ exhibited pro-atherogenic effects.