A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice
A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice
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DOI：
10.1194/jlr.m003665
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发表时间：
2010-06-01
影响因子：
6.5
通讯作者：
Azhar, Salman
中科院分区：
文献类型：
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作者：
Bielicki, John K.;Zhang, Haiyan;Azhar, Salman
在这里，我们报道了一种单螺旋肽（ATI-5261）的产生，它以近似天然载脂蛋白的K - m摩尔效率刺激细胞胆固醇外排。在高脂肪西方饮食（HFWD） 13-18周后，在5-7月龄的LDLR-/-和载脂蛋白（apo）E-/-小鼠中评估ATI-5261的抗动脉粥样硬化活性。每天腹腔注射ATI-5261 （30 mg/kg）治疗脂肪喂养的LDLR-/-小鼠6周后，动脉粥样硬化减少30%，根据病变面积覆盖主动脉（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）判断。在apoE（-/-）小鼠中，连续6周，每隔一天给药30 mg/kg / ip的肽减少了45%的动脉粥样硬化（病变面积= 15 +/- 7，对照为25 +/- 8%，P = 0.00016；斑块脂含量= 20 +/- 6，对照为32 +/- 8%，P < 0.0001）。使用ATI-5261: POPC复合物也能达到类似的动脉粥样硬化降低效果。单次腹腔注射ATI-5261在24-48小时内增加了巨噬细胞泡沫细胞到粪便的逆向胆固醇转运。总之，用有效的胆固醇外排肽ATI-5261相对短期治疗小鼠可减少实质性动脉粥样硬化。这是在严重高胆固醇血症/HFWD存在的情况下使用l -氨基酸肽实现的，并且在通过腹腔注射给药时不需要每天注射或配制磷脂。-Bielicki， J. K.，张h .， Y. Cortez， Y. Zheng， V. Narayanaswami， A. Patel， J. Johansson， S. Azhar。一种新的高密度脂蛋白模拟肽，能高效地刺激细胞胆固醇外排，大大减少小鼠动脉粥样硬化。[j] .油脂杂志。2010。51: 1496 - 1503。
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 similar to 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 similar to 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.-Bielicki, J. K., H. Zhang, Y. Cortez, Y. Zheng, V. Narayanaswami, A. Patel, J. Johansson, and S. Azhar. A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice. J. Lipid Res. 2010. 51: 1496-1503.