A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE −/− mice

Autor:	Hui Liu, Chao Zhong, Li Wang, Guangjun Bao, Jingman Ni, Xu Ouyang, Sanhu Gou, Beibei Li, Yun Zhang, Xinyue Chen
Rok vydání:	2020
Předmět:	0301 basic medicine Apolipoprotein B Phospholipid Peptide Mice 03 medical and health sciences chemistry.chemical_compound Apolipoproteins E 0302 clinical medicine In vivo Animals Pharmacology chemistry.chemical_classification Apolipoprotein A-I biology Cholesterol Atherosclerosis Research Papers Amino acid 030104 developmental biology chemistry Biochemistry biology.protein lipids (amino acids peptides and proteins) Efflux Peptides 030217 neurology & neurosurgery ATP Binding Cassette Transporter 1 Lipoprotein
Zdroj:	Br J Pharmacol
ISSN:	1476-5381 0007-1188
DOI:	10.1111/bph.15213
Popis:	Background and purpose Apolipoprotein A-I (apoA-I) mimetic peptides (AAMPs) are short peptides that can mimic the physiological effects of apoA-I, including the suppression of atherosclerosis by reversely transporting peripheral cholesterol to the liver. As the hydrophobicity of apoA-I is considered important for its lipid transport, novel AAMPs were designed and synthesized in this study by gradually increasing the hydrophobicity of the parent peptide, and their anti-atherosclerotic effects were tested. Experimental approach Seventeen new AAMPs (P1-P17) with incrementally increased hydrophobicity were designed and synthesized by replacing the amino acids 221-240 of apoA-I (VLESFKVSFLSALEEYTKKL). Their effects on cholesterol efflux were evaluated. Their cytotoxicity and haemolytic activity were also measured. The in vitro mechanism of the action of the new peptides was explored. Adult apolipoprotein E-/- mice were used to evaluate the anti-atherosclerotic activity of the best candidate, and the mechanistic basis of its anti-atherosclerotic effects was explored. Key results Seventeen new AAMPs (P1-P17) were synthesized, and their cholesterol efflux activity and cytotoxicity were closely related to their hydrophobicity. P12 (FLEKLKELLEHLKELLTKLL) was the best candidate and most strongly promoted cholesterol efflux among the non-toxic peptides (P1-P12). With its phospholipid affinity, P12 facilitated cholesterol transport through the ATP-binding cassette transporter A1. In vivo, P12 exhibited prominent anti-atherosclerotic activity via coupling with HDL. Conclusion and implications P12 featured adequate hydrophobicity, which ensured its efficient binding with cytomembrane phospholipids, cholesterol and HDL, and provided a basis for its ability to reversely transport cholesterol and treat atherosclerosis.
Databáze:	OpenAIRE
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