Lentz S R, Fernández J A, Griffin J H, Piegors D J, Erger R A, Malinow M R, Heistad D D
Veterans Affairs Medical Center, Departments of Internal Medicine and Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Arterioscler Thromb Vasc Biol. 1999 Jul;19(7):1744-50. doi: 10.1161/01.atv.19.7.1744.
To examine the effects of atherosclerosis on the protein C anticoagulant pathway in vivo, we measured anticoagulant responses to intravenous administration of human alpha-thrombin or activated protein C (APC) in cynomolgus monkeys. Two groups of monkeys were fed either a control diet (n=18) or an atherogenic diet (n=12) that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. A third group (n=8) was fed an atherogenic diet for 15 months, and then fed the atherogenic diet supplemented with B vitamins for 6 months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was higher in monkeys fed the atherogenic diet (9.6+/-1.0 micromol/L) than in monkeys fed the control diet (3.7+/-0.2 micromol/L) or the atherogenic diet with B vitamins (3.6+/-0.2 micromol/L) (P<0.001). Infusion of thrombin produced a much greater prolongation of the activated partial thromboplastin time in monkeys fed the control diet (52+/-10 seconds) than in monkeys fed the atherogenic diet either with (24+/-4 seconds) or without (27+/-5 seconds) supplemental B vitamins (P<0.02). Thrombin-dependent generation of circulating APC was higher in control (294+/-17 U/mL) than in atherosclerotic (240+/-14 U/mL) monkeys (P<0.05), although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin complexes were similar in each group. Injection of human APC produced a similar prolongation of the activated partial thromboplastin time in control (31+/-3 seconds) and atherosclerotic (29+/-2 seconds) monkeys. These findings provide evidence for impaired anticoagulation, due partly to decreased formation of APC, in atherosclerosis. The blunted anticoagulant response to thrombin in hypercholesterolemic monkeys was not corrected by supplementation with B vitamins.
为了在体内研究动脉粥样硬化对蛋白C抗凝途径的影响，我们测定了食蟹猴静脉注射人α-凝血酶或活化蛋白C（APC）后的抗凝反应。两组猴子分别喂食对照饮食（n = 18）或致动脉粥样硬化饮食（n = 12），后者可导致高胆固醇血症和中度高同型半胱氨酸血症。第三组（n = 8）先喂食致动脉粥样硬化饮食15个月，然后喂食补充了B族维生素的致动脉粥样硬化饮食6个月以纠正高同型半胱氨酸血症。喂食致动脉粥样硬化饮食的猴子血浆同型半胱氨酸水平（9.6±1.0微摩尔/升）高于喂食对照饮食的猴子（3.7±0.2微摩尔/升）或喂食补充B族维生素的致动脉粥样硬化饮食的猴子（3.6±0.2微摩尔/升）（P<0.001）。注射凝血酶后，喂食对照饮食的猴子活化部分凝血活酶时间延长幅度（52±10秒）远大于喂食补充（24±4秒）或未补充（27±5秒）B族维生素的致动脉粥样硬化饮食的猴子（P<0.02）。对照猴子（294±17 U/mL）中凝血酶依赖的循环APC生成高于动脉粥样硬化猴子（240±14 U/mL）（P<0.05），尽管每组中纤维蛋白原、纤溶酶原、D-二聚体和凝血酶-抗凝血酶复合物水平相似。注射人APC后，对照猴子（31±3秒）和动脉粥样硬化猴子（29±2秒）的活化部分凝血活酶时间延长相似。这些发现提供了证据，表明动脉粥样硬化中存在抗凝受损，部分原因是APC生成减少。高胆固醇血症猴子中对凝血酶的抗凝反应减弱并未因补充B族维生素而得到纠正。
