Kaul Sanjay, Coin Bryan, Hedayiti Amir, Yano Juliana, Cercek Bojan, Chyu Kuang-Y, Shah Prediman K
Vascular Physiology and Thrombosis Research Laboratory of the Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
J Am Coll Cardiol. 2004 Sep 15;44(6):1311-9. doi: 10.1016/j.jacc.2004.06.028.
In this study, we examined whether a reconstituted high-density lipoprotein (HDL) utilizing recombinant apolipoprotein A-I(Milano) (apo A-I(M))/phospholipid complex (PC) could restore normal endothelial function in hypercholesterolemic apolipoprotein (apo) E-null mice.
We have previously shown antiatherosclerotic and vasculoprotective effects of recombinant apo A-I(M).
A perfused vessel preparation was used to examine vascular responses in control wild-type, untreated, and treated apo E-null mice. Aortic tissue cholesterol content and platelet aggregation were also measured.
Endothelium-dependent vasodilator responses to acetycholine were significantly inhibited in untreated apo E-null mice compared with control wild-type mice (p < 0.001). Treatment of the mice for five weeks with once every-other-day intravenous bolus injections of apo A-I(M)/PC restored endothelium-dependent dilation in a dose-dependent manner (p < 0.01 at 80 mg/kg dose). The improvement in endothelial function was associated with a reduction in aortic cholesterol content and reduced platelet aggregability and occurred despite severe and persistent hypercholesterolemia. Neither treatment with free protein nor phospholipid carrier alone produced any significant effects. We performed additional experiments in vitro in isolated rabbit carotid arteries to compare the effects on lysophosphatidylcholine (LPC)-induced endothelial dysfunction. Treatment with apo A-I(M)/PC prevented impairment of endothelium-dependent vasodilator responses to acetylcholine to a greater degree than either wild-type apo A-I or plasma-derived HDL.
Our results indicate a rapid improvement in endothelial dysfunction with recombinant apo A-I(M)/PC that is associated with mobilization of tissue cholesterol. Taken together with previously established antiatherosclerotic and antithrombotic effects, these findings suggest significant vasculoprotective effects with apo A-I(M)/PC therapy.
在本研究中，我们检测了利用重组载脂蛋白A-I（米兰）（apo A-I(M)）/磷脂复合物（PC）重构的高密度脂蛋白（HDL）是否能恢复高胆固醇血症载脂蛋白（apo）E基因敲除小鼠的正常内皮功能。
我们之前已证明重组apo A-I(M)具有抗动脉粥样硬化和血管保护作用。
采用灌注血管制备方法检测对照野生型、未治疗及治疗后的apo E基因敲除小鼠的血管反应。还测量了主动脉组织胆固醇含量和血小板聚集情况。
与对照野生型小鼠相比，未治疗的apo E基因敲除小鼠对乙酰胆碱的内皮依赖性血管舒张反应显著受到抑制（p < 0.001）。每隔一天静脉推注apo A-I(M)/PC对小鼠进行为期五周的治疗，以剂量依赖方式恢复了内皮依赖性舒张（80 mg/kg剂量时p < 0.01）。内皮功能的改善与主动脉胆固醇含量降低以及血小板聚集性降低相关，尽管存在严重且持续的高胆固醇血症，这种改善依然发生。单独使用游离蛋白或磷脂载体治疗均未产生任何显著效果。我们在体外对分离的兔颈动脉进行了额外实验，以比较对溶血磷脂酰胆碱（LPC）诱导的内皮功能障碍的影响。与野生型apo A-I或血浆来源的HDL相比，apo A-I(M)/PC治疗对乙酰胆碱诱导的内皮依赖性血管舒张反应的损害具有更大程度的预防作用。
我们的结果表明，重组apo A-I(M)/PC能使内皮功能障碍迅速改善，这与组织胆固醇的动员有关。结合先前确立的抗动脉粥样硬化和抗血栓形成作用，这些发现提示apo A-I(M)/PC治疗具有显著的血管保护作用。
