Abstract
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.
Highlights
Plasma levels of high density lipoprotein (HDL) inversely correlate with the incidence of cardiovascular disease and HDL is believed to protect against development of atherosclerosis
The most direct approach is the intravenous infusion of HDL, usually in the form of reconstituted HDL; a variation of this approach is the infusion of apolipoprotein A–I mimetic peptides
The original concept that led to the development of an apolipoprotein A–I (apoA-I) mimetic peptide was based on the assumption that the functional properties of apoA-I, the predominant apolipoprotein of HDL, are derived from its secondary structure, a series of 22-mer amphipathic a-helices linked by proline residues [3]
Summary
Plasma levels of high density lipoprotein (HDL) inversely correlate with the incidence of cardiovascular disease and HDL is believed to protect against development of atherosclerosis. Several peptides were tested in animal models of atherosclerosis and were found to be atheroprotective [5,6,7,8,9] The mechanisms behind these atheroprotective effects are not completely understood: in the majority of cases, infusion of the peptides minimally affected plasma levels of HDL cholesterol, yet improved various facets of HDL functionality. This makes it likely that after infusion the peptides may bind to plasma lipoproteins and act by affecting metabolism and functional properties of lipoproteins [10,11]. Other modifications included the ‘‘stapling’’ of the peptides to stabilize their secondary structure [14]
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