Apolipoprotein E mimetic peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits
Apolipoprotein E mimetic peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits
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DOI：
10.1161/circulationaha.104.497107
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发表时间：
2005-06-14
期刊：
影响因子：
37.8
通讯作者：
Anantharamaiah, GM
中科院分区：
文献类型：
--
作者：
Gupta, H;White, CR;Anantharamaiah, GM
背景-这些研究旨在确定与载脂蛋白(Apo)E受体结合域相连的A类两亲性螺旋的双结构域多肽(ac-he-18A-NH2)是否具有降血脂和抗炎特性。方法和结果：单剂(15 mg/kg iv)的ac-He-18A-NH2包含与apo A-I模拟肽18A共价连接的LRKLRKRRLLR(apo A-I模拟肽18A)不仅能降低血浆胆固醇水平(基线，+/-29.0 mg/dL比287.7+/-22.0 mg/dL)P<；0.001)，在渡边遗传性高脂血症兔模型中，还可显著改善动脉内皮功能。这一改善与氧化应激的两个标记物的减少有关。首先，血浆脂质过氧化氢含量显著降低，这一效果与高密度脂蛋白对氧磷酶活性增加5倍有关。其次，一氧化氮的清除剂超氧阴离子在这些动物的动脉中的形成也显著减少。结论-由于血脂异常和内皮功能障碍是动脉粥样硬化疾病过程的共同特征，这种独特的双结构域多肽具有理想的复合性质，可以改善动脉粥样硬化的关键促成因素。
Background - These studies were designed to determine whether the dual-domain peptide with a class A amphipathic helix linked to the receptor-binding domain of apolipoprotein (apo) E (Ac-hE-18A-NH2) possesses both antidyslipidemic and antiinflammatory properties.Methods and Results - A single bolus (15 mg/kg IV) of Ac-hE-18A-NH2 that contains LRKLRKRLLR (141- to 150-residue region of apo E) covalently linked to apo A-I mimetic peptide 18A not only reduced plasma cholesterol levels ( baseline, 562 +/- 29.0 mg/dL versus 287.7 +/- 22.0 mg/dL at 18 hours, P < 0.001) in the Watanabe heritable hyperlipidemic rabbit model but also significantly improved arterial endothelial function. This improvement was associated with a reduction in 2 markers of oxidative stress. First, the plasma lipid hydroperoxide content was reduced significantly, an effect associated with a 5-fold increase in HDL paraoxonase activity. Second, the formation of superoxide anion, a scavenger of nitric oxide, was also significantly reduced in arteries of these animals.Conclusions - Because dyslipidemia and endothelial dysfunction are common features of the atherosclerotic disease process, this unique dual-domain peptide has ideal composite properties that ameliorate key contributory factors to atherosclerosis.