Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267, University of California, Berkeley, CA 94720, USA.
J Lipid Res. 2010 Jun;51(6):1496-503. doi: 10.1194/jlr.M003665. Epub 2010 Jan 14.
Here, we report the creation of a single-helix peptide (ATI-5261) that stimulates cellular cholesterol efflux with K(m) molar efficiency approximating native apolipoproteins. Anti-atherosclerosis activity of ATI-5261 was evaluated in LDLR(-/-) and apolipoprotein (apo)E(-/-) mice approximately 5-7 months of age, following 13-18 weeks on a high-fat Western diet (HFWD). Treatment of fat-fed LDLR(-/-) mice with daily intraperitoneal injections of ATI-5261 (30 mg/kg) for 6 weeks reduced atherosclerosis by 30%, as judged by lesion area covering the aorta (7.9 +/- 2 vs.11.3 +/- 2.5% control, P = 0.011) and lipid-content of aortic sinus plaque (25 +/- 5.8 vs. 33 +/- 4.9% control, P = 0.014). In apoE(-/-) mice, the peptide administered 30 mg/kg ip on alternate days for 6 weeks reduced atherosclerosis by approximately 45% (lesion area = 15 +/- 7 vs. 25 +/- 8% control, P = 0.00016; plaque lipid-content = 20 +/- 6 vs. 32 +/- 8% control, P < 0.0001). Similar reductions in atherosclerosis were achieved using ATI-5261:POPC complexes. Single intraperitoneal injection of ATI-5261 increased reverse cholesterol transport from macrophage foam-cells to feces over 24-48 h. In summary, relatively short-term treatment of mice with the potent cholesterol efflux peptide ATI-5261 reduced substantial atherosclerosis. This was achieved using an L-amino acid peptide, in the presence of severe hypercholesterolemia/HFWD, and did not require daily injections or formulation with phospholipids when administered via intraperitoneal injection.
在这里，我们报告了一种单螺旋肽（ATI-5261）的创建，该肽以接近天然载脂蛋白的 K(m)摩尔效率刺激细胞胆固醇流出。在大约 5-7 个月大的 LDLR(-/-)和载脂蛋白（apo）E(-/-)小鼠中，在用高脂肪西方饮食（HFWD）喂养 13-18 周后，评估了 ATI-5261 的抗动脉粥样硬化活性。用每日腹腔内注射 ATI-5261（30mg/kg）治疗高脂喂养的 LDLR(-/-)小鼠 6 周，可使动脉粥样硬化减少 30%，根据主动脉（7.9 +/- 2%比 11.3 +/- 2.5%对照，P = 0.011）和主动脉窦斑块脂质含量（25 +/- 5.8%比 33 +/- 4.9%对照，P = 0.014）来判断。在 apoE(-/-)小鼠中，肽以 30mg/kg 剂量每两天腹腔内给药 6 周，可使动脉粥样硬化减少约 45%（病变面积= 15 +/- 7%比 25 +/- 8%对照，P = 0.00016；斑块脂质含量= 20 +/- 6%比 32 +/- 8%对照，P < 0.0001）。使用 ATI-5261:POPC 复合物可实现类似的动脉粥样硬化减少。单次腹腔内注射 ATI-5261 可在 24-48 小时内增加从巨噬细胞泡沫细胞到粪便的胆固醇逆向转运。总之，用有效的胆固醇流出肽 ATI-5261 对小鼠进行相对短期的治疗可显著减少动脉粥样硬化。这是使用 L-氨基酸肽在严重高胆固醇血症/HFWD 存在的情况下实现的，并且在通过腹腔内注射给药时不需要每日注射或用磷脂制剂。
