Yasunori Suematsu1, Emi Kawachi2, Yoshiaki Idemoto1, Yoshino Matsuo1, Takashi Kuwano1, Ken Kitajima1, Satoshi Imaizumi2, Akira Kawamura3, Keijiro Saku4, Yoshinari Uehara5, Shin-Ichiro Miura6. 1. Department of Cardiology, Fukuoka University School of Medicine, Japan. 2. Clinical Research and Ethics Center, Fukuoka University School of Medicine, Japan. 3. Center for Graduate Clinical Practice, Fukuoka University Hospital, Fukuoka, Japan. 4. General Medical Research Center, Fukuoka University School of Medicine, Japan. 5. Graduate School of Sports and Health Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: ueharay@fukuoka-u.ac.jp. 6. Department of Cardiology, Fukuoka University School of Medicine, Japan. Electronic address: miuras@cis.fukuoka-u.ac.jp.
Abstract
BACKGROUND: Apolipoprotein (Apo)A-I is a major protein component of high-density lipoprotein (HDL) that causes cholesterol efflux from peripheral cells through ATP-binding cassette transporter A1 (ABCA1) and the generation of HDL. Furthermore, it has a possible protective function against atherosclerotic cardiovascular disease (ASCVD). We previously developed a novel ApoA-I mimetic peptide without phospholipids (Fukuoka University ApoA-I Mimetic Peptide, FAMP). According to our previous studies, FAMP had an anti-arteriosclerotic effect. Since the required dose and reaction time of conventional FAMP were relatively large and short, respectively, we newly developed an improved FAMP (i-FAMP). METHODS AND RESULTS: We synthesized four candidate i-FAMPs, i-FAMP-D1, -D2, -D3 and -D4, and examined which i-FAMP has greater cholesterol efflux capacity than FAMP in A172 human glioblastoma cells transiently transfected with human ABCA1 cDNA. Only i-FAMP-D1 showed significantly greater cholesterol efflux capacity than conventional FAMP. i-FAMP-D1 formed stronger α-helical conformations than FAMP as assessed by circular dichroism spectra. Thus, we selected i-FAMP-D1 for further experiments. i-FAMP-D1 had a greater atheroprotective effect than FAMP in ApoE knockout mice. In addition, i-FAMP-D1 activated cholesterol efflux from macrophage to HDL more strongly than FAMP and increased cholesterol excretion from liver to feces. CONCLUSION: These results suggest that i-FAMP-D1 has a stronger anti-atherosclerotic effect than conventional FAMP.
BACKGROUND: Apolipoprotein (Apo)A-I is a major protein component of high-density lipoprotein (HDL) that causes cholesterol efflux from peripheral cells through ATP-binding cassette transporter A1 (ABCA1) and the generation of HDL. Furthermore, it has a possible protective function against atherosclerotic cardiovascular disease (ASCVD). We previously developed a novel ApoA-I mimetic peptide without phospholipids (Fukuoka University ApoA-I Mimetic Peptide, FAMP). According to our previous studies, FAMP had an anti-arteriosclerotic effect. Since the required dose and reaction time of conventional FAMP were relatively large and short, respectively, we newly developed an improved FAMP (i-FAMP). METHODS AND RESULTS: We synthesized four candidate i-FAMPs, i-FAMP-D1, -D2, -D3 and -D4, and examined which i-FAMP has greater cholesterol efflux capacity than FAMP in A172 humanglioblastoma cells transiently transfected with humanABCA1 cDNA. Only i-FAMP-D1 showed significantly greater cholesterol efflux capacity than conventional FAMP. i-FAMP-D1 formed stronger α-helical conformations than FAMP as assessed by circular dichroism spectra. Thus, we selected i-FAMP-D1 for further experiments. i-FAMP-D1 had a greater atheroprotective effect than FAMP in ApoE knockout mice. In addition, i-FAMP-D1 activated cholesterol efflux from macrophage to HDL more strongly than FAMP and increased cholesterol excretion from liver to feces. CONCLUSION: These results suggest that i-FAMP-D1 has a stronger anti-atherosclerotic effect than conventional FAMP.
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