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

Gou, Sanhu; Wang, Li; Zhong, Chao; Chen, Xinyue; Ouyang, Xu; Li, Beibei; Bao, Guangjun; Liu, Hui; Zhang, Yun; Ni, Jingman

BACKGROUND AND PURPOSE Apolipoprotein A-I (apoA-I) mimetic peptides (AMPs) 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 AMPs 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 AMPs (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 hemolytic activity were also measured. The in vitro mechanism of the action of the new peptides were 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 were explored. KEY RESULTS Seventeen new AMPs (P1-P17) were synthesized and their cholesterol efflux activity and cytotoxicity were closely related to their hydrophobicity. P12 (FLEKLKELLEHLKELLTKLL), as the best candidate, most strongly promoted cholesterol efflux among the non-toxic peptides (P1-P12). With its phospholipid affinity, P12 can effortlessly facilitate cholesterol transport through ATP-binding cassette transporter A1. In vivo, P12 exhibited prominent anti-atherosclerotic activity via coupling with HDL. CONCLUSIONS AND IMPLICATIONS P12 featured proper 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.