An apolipoprotein A-I mimetic peptide designed with a reductionist approach stimulates reverse cholesterol transport and reduces atherosclerosis in mice

• Published in: PloS one Vol. 8; no. 7; p. e68802
• Main Authors: Ditiatkovski, Michael, D'Souza, Wilissa, Kesani, Rajitha, Chin-Dusting, Jaye, de Haan, Judy B, Remaley, Alan, Sviridov, Dmitri
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-07-2013; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Analysis; Animal models; Animals; Aorta; Aortic arch; Apolipoprotein A; Apolipoprotein A-I; Apolipoprotein A-I - blood; Apolipoprotein A-I - chemistry; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological Transport - drug effects; Biology; Biomimetics; Cholesterol; Cholesterol - metabolism; Diabetes; Disease Models, Animal; Efflux; Elk; Health aspects; Heart; High density lipoprotein; High fat diet; In vivo methods and tests; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Laboratory animals; Lipids; Lipoproteins; Lipoproteins (high density); Male; Medical research; Medicine; Metabolism; Metabolites; Mice; Mice, Knockout; Oxidation; Oxidation-Reduction - drug effects; Oxidizing agents; Particulates; Peptides; Peptides - chemistry; Peptides - pharmacokinetics; Peptides - pharmacology; Plaques; Rodents; Transport; Triglycerides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068802

Apolipoprotein A-I (apoA-I) mimetic peptides are considered a promising novel therapeutic approach to prevent and/or treat atherosclerosis. An apoA-I mimetic peptide ELK-2A2K2E was designed with a reductionist approach and has shown exceptional activity in supporting cholesterol efflux but modest anti-inflammatory and anti-oxidant properties in vitro. In this study we compared these in vitro properties with the capacity of this peptide to modify rates of reverse cholesterol transport and development of atherosclerosis in mouse models. The peptide enhanced the rate of reverse cholesterol transport in C57BL/6 mice and reduced atherosclerosis in Apoe(-/-) mice receiving a high fat diet. The peptide modestly reduced the size of the plaques in aortic arch, but was highly active in reducing vascular inflammation and oxidation. Administration of the peptide to Apoe(-/-) mice on a high fat diet reduced the levels of total, high density lipoprotein and non-high density lipoprotein cholesterol and triglycerides. It increased the proportion of smaller HDL particles in plasma at the expense of larger HDL particles, and increased the capacity of the plasma to support cholesterol efflux. Thus, ELK-2A2K2E peptide reduced atherosclerosis in Apoe(-/-) mice, however, the functional activity profile after chronic in vivo administration was different from that found in acute in vitro studies.