Structure/function relationships of apolipoprotein A-I mimetic peptides: Implications for antiatherogenic activities of high-density lipoprotein

Wilissa D'Souza, John A. Stonik, Andrew Murphy, Steven J. Demosky, Amar A. Sethi, Xiao L. Moore, Jaye Chin-Dusting, Alan T. Remaley, Dmitri Sviridov

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69 Citations (Scopus)

Abstract

Rationale: Apolipoprotein (apoA)-I mimetic peptides are a promising type of antiatherosclerosis therapy, but how the structural features of these peptides relate to the multiple antiatherogenic functions of HDL is poorly understood. Objective: To establish structure/function relationships of apoA-I mimetic peptides with their antiatherogenic functions. Methods and results: Twenty-two bihelical apoA-I mimetic peptides were investigated in vitro for the capacity and specificity of cholesterol efflux, inhibition of inflammatory response of monocytes and endothelial cells, and inhibition of low-density lipoprotein (LDL) oxidation. It was found that mean hydrophobicity, charge, size of hydrophobic face, and angle of the link between the helices are the major factors determining the efficiency and specificity of cholesterol efflux. The peptide with optimal parameters was more effective and specific toward cholesterol efflux than human apoA-I. Charge and size of hydrophobic face were also the major factors affecting antiinflammatory properties, and the presence of cysteine and histidine residues was the main factor determining antioxidant properties. There was no significant correlation between capacities of the peptides to support individual functions; each function had its own optimal set of features. Conclusions: None of the peptides was equally effective in all the antiatherogenic functions tested, suggesting that different functions of HDL may have different mechanisms and different structural requirements. The results do suggest, however, that rationalizing the design of apoA-I mimetic peptides may improve their therapeutic value and may lead to a better understanding of mechanisms of various antiatherogenic functions of HDL.

Original languageEnglish
Pages (from-to)217-227
Number of pages11
JournalCirculation Research
Volume107
Issue number2
DOIs
Publication statusPublished - 23 Jul 2010
Externally publishedYes

Keywords

  • atherosclerosis
  • high-density lipoprotein
  • mimetic peptides

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