FAMP, a Novel ApoA‐I Mimetic Peptide, Suppresses Aortic Plaque Formation Through Promotion of Biological HDL Function in ApoE‐Deficient Mice

Abstract

BackgroundApolipoprotein (apo) A‐I is a major high‐density lipoprotein (HDL) protein that causes cholesterol efflux from peripheral cells through the ATP‐binding cassette transporter A1 (ABCA1), thus generating HDL and reversing the macrophage foam cell phenotype. Pre‐β1 HDL is the smallest subfraction of HDL, which is believed to represent newly formed HDL, and it is the most active acceptor of free cholesterol. Furthermore it has a possible protective function against cardiovascular disease (CVD). We developed a novel apoA‐I mimetic peptide without phospholipids (Fukuoka University ApoA‐I Mimetic Peptide, FAMP).Methods and ResultsFAMP type 5 (FAMP5) had a high capacity for cholesterol efflux from A172 cells and mouse and human macrophages in vitro, and the efflux was mainly dependent on ABCA1 transporter. Incubation of FAMP5 with human HDL or whole plasma generated small HDL particles, and charged apoA‐I‐rich particles migrated as pre‐β HDL on agarose gel electrophoresis. Sixteen weeks of treatment with FAMP5 significantly suppressed aortic plaque formation (scrambled FAMP, 31.3±8.9% versus high‐dose FAMP5, 16.2±5.0%; P<0.01) and plasma C‐reactive protein and monocyte chemoattractant protein‐1 in apoE‐deficient mice fed a high‐fat diet. In addition, it significantly enhanced HDL‐mediated cholesterol efflux capacity from the mice.ConclusionsA newly developed apoA‐I mimetic peptide, FAMP, has an antiatherosclerotic effect through the enhancement of the biological function of HDL. FAMP may have significant atheroprotective potential and prove to be a new therapeutic tool for CVD.

Therapeutic Approaches to the Regulation of Metabolism of High-Density Lipoprotein

“…100 FAMP Recently, a peptide that mimics human apoA-I without complexing with PL, FAMP (Fukuoka University ApoA-I Mimetic Peptide), has been shown to enhance the function of HDL, and suppress aortic plaque formation in apoE-knockout mice fed a high-fat diet. 101 FAMP markedly increases pre-β HDL, and also increases overall cholesterol efflux from peripheral tissues. FAMP may enhance cellular cholesterol efflux by 2 mechanisms (Figure 5): (1) internalization and transcytosis in macrophages or aortic endothelial cells, and the removal of intracellular cholesterol, and (2) physical interactions between FAMP and ABCA1 to transport intracellular cholesterol to the circulation, and this latter mechanism may be predominant.…”

“…FAMP, a novel apoA-I mimetic peptide that is small with 24 amino acids, has been shown to enhance the function of high-density lipoprotein (HDL). 101 FAMP may induce cellular cholesterol efflux by 2 mechanisms: (1) internalization and transcytosis in macrophages or aortic endothelial cells, and the removal of intracellular cholesterol (Upper middle panel), and (2) physical interactions between FAMP and ABCA1 to transport intracellular cholesterol to the circulation (Lower middle panel), and this latter mechanism may be predominant. HDL-Directed Therapies and Exercise…”

Stabilization of high-risk plaques

“…ApoA-I mimetic peptides are a major example; the 5F peptide inhibits the formation of aortic plaque in mice receiving a high-fat diet, which is the first in vivo demonstration that apoA-I mimetic peptides have atheroprotective properties (74). An ApoA-I mimetic peptide that contains 24 amino acids without phospholipids, Fukuoka University ApoA-I Mimetic Peptide (FAMP), enhanced HDL function and suppressed aortic plaque formation in apoE KO mice (75). In human studies, intravenous administration of ETC-216 (an apoA-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complex) was associated with the significant regression of coronary atherosclerotic plaques as measured by IVUS (76).…”

High-Density Lipoprotein Mimetics: a Therapeutic Tool for Atherosclerotic Diseases

“…, P 00.01 vs. BSA; , P 00.01 vs. apoA-I; , P 00.01 vs. FAMP; , P 00.05 vs. FAMP in mock; , P 0.01 vs. FAMP in mock; , P 00.01 vs. apoA-I in mock. Graphs modified from the paper by Uehara et al 38) . 16 weeks has resulted in a marked inhibition of atherosclerotic plaque progression, whereas plasma HDL cholesterol was not increased in ApoE-deficient mice fed a high-fat diet 38) .…”