5A Apolipoprotein Mimetic Peptide Promotes Cholesterol Efflux and Reduces Atherosclerosis in Mice
5A Apolipoprotein Mimetic Peptide Promotes Cholesterol Efflux and Reduces Atherosclerosis in Mice
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DOI：
10.1124/jpet.110.167890
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发表时间：
2010-08-10
影响因子：
3.5
通讯作者：
Remaley, Alan T.
中科院分区：
文献类型：
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作者：
Amar, Marcelo J. A.;D'Souza, Wilissa;Remaley, Alan T.
静脉注射载脂蛋白（apo）A-I与磷脂复合物已被证明可以迅速减少动物模型和人体中的斑块大小。短的合成的两亲性肽可以模拟apoA-I的抗动脉粥样硬化性质，并已被提议作为替代治疗剂。在这项研究中，我们研究了5A肽的动脉粥样硬化保护作用，5A肽是一种双螺旋两亲性肽，通过ATP结合盒转运蛋白1（ABCA 1）特异性地从细胞中排出胆固醇。5A刺激ABCA 1介导的从细胞的流出增加3.5倍，并且在将其与磷脂复合（1：7 mol/mol）后增加额外的2.5倍。5A-棕榈酰油酰磷脂酰胆碱（POPC），但不是游离5A，也被发现促进胆固醇流出ABCG 1。当与人血清孵育时，5A-POPC主要与高密度脂蛋白（HDL）结合，但也与低密度脂蛋白（LDL）结合，并促进胆固醇从LDL转移到HDL。给apoE基因敲除（KO）小鼠静脉注射5A-POPC（30 mg/kg）后24 h，HDL中胆固醇（181%）和磷脂（219%）含量均显著升高。通过体内胆固醇同位素稀释研究和监测胆固醇从放射性标记的巨噬细胞到粪便的通量，观察到5A-POPC处理增加了胆固醇的反向转运。在三项单独的研究中，当与各种磷脂复合时，5A使apoE-KO小鼠中的主动脉斑块表面积减少29至53%（每组n = 8; p <0.02）。在这些研究期间未观察到给药的毒性体征。总之，5A在体外和体内均促进胆固醇流出，并减少apoE-KO小鼠中的动脉粥样硬化，表明其可能是apoA-I用于HDL治疗的有用替代物。
Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy.