Li D, Weng S, Yang B, Zander D S, Saldeen T, Nichols W W, Khan S, Mehta J L
Department of Medicine, University of Florida College of Medicine, the VA Medical Center, Gainesville, Florida32610, USA.
Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):378-83. doi: 10.1161/01.atv.19.2.378.
The mutant form of human apoA1, known as apoA1 Milano, is formed as a result of arginine 173 to cysteine substitution and inhibits experimental atherosclerosis in cholesterol-fed animals. This study was designed to determine if apoA1 Milano would modify arterial thrombogenesis. Sprague Dawley rats were intravenously administered the carrier alone (n=8) or apoA1 Milano (20 mg. kg-1. d-1 for 4 to 10 days, n=17). The abdominal cavity was opened, and the abdominal aorta was isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was recorded continuously. In carrier-treated rats, an occlusive platelet-fibrin-rich thrombus was formed in 21.2+/-4.1 (mean+/-SD) minutes. Treatment of rats with apoA1 Milano markedly delayed time to thrombus formation (38.8+/-11.9 versus 21.2+/-4.1 minutes, P<0. 01), inhibited platelet aggregation (25+/-7% versus 50+/-11%, P<0. 01), and reduced weight of the thrombus (18.5+/-1.8 versus 23.7+/-2. 3 mg/cm, P<0.01). Total cholesterol and HDL levels remained similar in both groups of rats, but plasma apoA1 Milano levels were elevated in apoA1 Milano-treated rats. In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis.
人类载脂蛋白A1的突变形式，即载脂蛋白A1米兰突变体，是由精氨酸173被半胱氨酸取代形成的，可抑制胆固醇喂养动物的实验性动脉粥样硬化。本研究旨在确定载脂蛋白A1米兰突变体是否会改变动脉血栓形成。将斯普拉格-道利大鼠静脉注射单独的载体（n = 8）或载脂蛋白A1米兰突变体（20 mg·kg-1·d-1，持续4至10天，n = 17）。打开腹腔，分离腹主动脉。将浸有35%三氯化铁的沃特曼滤纸包裹在主动脉表面，并持续记录主动脉血流。在接受载体治疗的大鼠中，在21.2±4.1（平均值±标准差）分钟内形成了富含血小板-纤维蛋白的闭塞性血栓。用载脂蛋白A1米兰突变体治疗大鼠显著延迟了血栓形成时间（38.8±11.9分钟对21.2±4.1分钟，P<0.01），抑制了血小板聚集（25±7%对50±11%，P<0.01），并减轻了血栓重量（18.5±1.8对23.7±2.3 mg/cm，P<0.01）。两组大鼠的总胆固醇和高密度脂蛋白水平保持相似，但在接受载脂蛋白A1米兰突变体治疗的大鼠中，血浆载脂蛋白A1米兰突变体水平升高。在体外研究中，血小板与载脂蛋白A1米兰突变体孵育可使二磷酸腺苷诱导的血小板聚集降低约50%，但载脂蛋白A1米兰突变体对血管反应性无直接影响。本研究为血小板在血栓形成中的关键作用提供了进一步证据。使用载脂蛋白A1米兰突变体为抑制动脉血栓形成提供了一种新方法。
