Apolipoprotein A-I mimetic peptides
Apolipoprotein A-I mimetic peptides
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DOI：
10.1161/01.atv.0000165694.39518.95
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发表时间：
2005-07-01
影响因子：
8.7
通讯作者：
Fogelman, AM
中科院分区：
文献类型：
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作者：
Navab, M;Anantharamaiah, GM;Fogelman, AM
尽管氨基酸组成相同，但由于疏水表面氨基酸顺序的不同导致A类两亲性螺旋肽的差异，导致抗炎性质的实质性差异。其中一种多肽是载脂蛋白A-I(apoA-I)的模拟物D-4F。当D-4F口服给小鼠和猴子时，可引起前β-高密度脂蛋白的形成，改善高密度脂蛋白介导的胆固醇外流，降低脂蛋白脂质过氧化氢，提高对氧磷酶活性，并将高密度脂蛋白从促炎转化为抗炎。在载脂蛋白E(ApoE)缺失的小鼠中，D-4F增加了巨噬细胞的胆固醇反向转运。口服D-4F可减轻载脂蛋白E缺失和低密度脂蛋白受体缺失小鼠的动脉粥样硬化。在体外，当D-4F以纳摩尔浓度加入人血浆中时，可导致前β-高密度脂蛋白的形成，减少脂蛋白脂质过氧化氢，增加对氧磷酶活性，并将高密度脂蛋白从促炎转化为抗炎。不同A类两亲性螺旋肽的理化性质和体外激活卵磷脂胆固醇酰基转移酶(LCAT)的能力不能预测体内的生物活性。相比之下，使用培养的人动脉壁细胞来评估这些多肽更能预测它们在体内的疗效。我们的结论是，不同A类两亲性螺旋肽的抗炎性能取决于多肽疏水性表面的细微差异，这决定了多肽隔离炎性脂类的能力。这些差异似乎太微妙了，不能仅基于物理化学性质来预测疗效。然而，了解这些物理化学性质为活性多肽的作用机制提供了解释。
Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from proinflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-beta HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.