Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity.
Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity.
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DOI：
10.1161/circresaha.113.301112
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发表时间：
2013-06-21
影响因子：
20.1
通讯作者：
Wang N
中科院分区：
文献类型：
--
作者：
Murphy AJ;Funt S;Gorman D;Tall AR;Wang N
输注apoA-I、模拟肽或HDL仍然是治疗动脉粥样硬化性冠状动脉疾病的有希望的方法。然而，快速清除导致需要重复给予大量材料并限制有效血浆浓度。由于纯化蛋白质的聚乙二醇化通常用作增加其在循环中的半衰期的方法，因此我们确定apoA-I或HDL的聚乙二醇化是否会增加其血浆半衰期，进而增加其抗动脉粥样硬化的潜力。使用脂质贫乏的apoA-I的初始聚乙二醇化尝试显示出形成多聚乙二醇化（PEG）物质的显著趋势，其具有降低的促进胆固醇从巨噬泡沫细胞流出的能力。然而，人holo-HDL或重构磷脂/apoA-I颗粒（rHDL）的聚乙二醇化导致apoA-I的选择性N-末端单聚乙二醇化，同时完全保留胆固醇流出活性。在注射到高胆固醇血症Apoe−/−小鼠中后，估计PEG-rHDL的血浆清除率;与非聚乙二醇化rHDL中的apoA-I相比，注射PEG-rHDL后聚乙二醇化apoA-I的半衰期增加约7倍。与非聚乙二醇化rHDL相比，将PEG-rHDL（40 mg/kg）输注到高胆固醇血症Apoe−/−小鼠中导致对骨髓髓样祖细胞增殖和单核细胞增多的更明显抑制，以及减少动脉粥样硬化和稳定的斑块表型。我们描述了一种新的方法，有效的单聚乙二醇化的载脂蛋白A-I的HDL颗粒，其中脂质结合似乎保护对聚乙二醇化的关键功能残基。载脂蛋白A-I在rHDL中的聚乙二醇化显著增加其血浆半衰期并增强体内抗动脉粥样硬化性质。
Infusions of apoA-I, mimetic peptides or HDL remain a promising approach to treatment of atherosclerotic coronary disease. However, rapid clearance leads to a requirement for repeated administration of large amounts of material and limits effective plasma concentrations. Since pegylation of purified proteins is commonly used as a method to increase their half-life in the circulation, we determined whether pegylation of apoA-I or HDL would increase its plasma half-life and in turn its anti-atherogenic potential. Initial pegylation attempts using lipid-poor apoA-I showed a marked tendency to form multi-pegylated (PEG) species with reduced ability to promote cholesterol efflux from macrophage foam cells. However, pegylation of human holo-HDL or reconstituted phospholipid/apoA-I particles (rHDL) led to selective N-terminal mono-pegylation of apoA-I with full preservation of cholesterol efflux activity. The plasma clearance of PEG-rHDL was estimated following injection into hypercholesterolemic Apoe−/− mice; the half-life of pegylated apoA-I following injection of PEG-rHDL was increased about 7-fold compared to apoA-I in non-pegylated rHDL. Compared to non-pegylated rHDL, infusion of PEG-rHDL (40 mg/kg) into hypercholesterolemic Apoe−/− mice led to more pronounced suppression of bone marrow myeloid progenitor cell proliferation and monocytosis, as well as reduced atherosclerosis and a stable plaque phenotype. We describe a novel method for effective mono-pegylation of apoA-I in HDL particles, in which lipid binding appears to protect against pegylation of key functional residues. Pegylation of apoA-I in rHDL markedly increases its plasma half-life and enhances anti-atherogenic properties in vivo.