HYPERHOMOCYST(E)INEMIA ON VASCULAR FUNCT IN ATHEROSCLEROTIC MONKEYS

血浆同型半胱氨酸（H（e））升高与 动脉粥样硬化性血管疾病的风险增加。 我们观察到 中度缺血性脑血管病猴的血管功能受损 高同型半胱氨酸血症（血浆H（e）> 10 fM）（J Clin Invest 98：24-29， 1996年）。 在这项研究中，我们测试了假设， 高同型半胱氨酸血症导致血管功能障碍 动脉粥样硬化的猴子 食蟹猴被喂食致动脉粥样硬化的 饮食，已知产生高胆固醇血症和中度 高同型半胱氨酸血症。 16个月后， 每日补充B族维生素（5 mg叶酸，400 fg B12和20 mg B6）6个月。 血浆H（e）从12.8 q 2.8降至3.5 q 0.3 fM（n=9;平均q SE）; p <0.01），但 血浆胆固醇没有变化（522 q 63 vs. 514 q 41 mg/dL; p >0.05）。 动脉内胶原蛋白的反应是，血液流向腿部 分别下降了30 q 3%和38 q 5%， 补充维生素（P <0.05）。 体内反应 内皮依赖性血管扩张剂（乙酰胆碱或ADP）， 在基线时受损，添加维生素后没有改善。 在离体颈动脉中，对乙酰胆碱的松弛改善 只有在补充维生素后才有轻微的变化。 离体血栓调节蛋白 抗凝血活性是3倍高， 致动脉粥样硬化饮食（含或不含B族维生素） （p <0.05）。 我们的结论是猴子的动脉粥样硬化与 血栓调节蛋白活性升高， 血浆H（e）不足以恢复正常的血管功能 持续性高胆固醇血症

Elevation of plasma homocyst(e)ine (H(e)) is associated with increased risk for atherosclerotic vascular disease. We have observed impaired vascular function in monkeys with moderate hyperhomo-cyst(e)inemia (plasma H(e) > 10 fM) (J Clin Invest 98:24-29, 1996). In this study we tested the hypothesis that hyperhomocyst(e)inemia contributes to vascular dysfunction in atherosclerotic monkeys. Cynomolgus monkeys were fed an atherogenic diet that is known to produce both hypercholesterolemia and moderate hyperhomocyst(e)inemia. After 16 months, the atherogenic diet was supplemented with B vitamins daily (5 mg folic acid, 400 fg B12 and 20 mg B6) for 6 months. Plasma H(e) decreased from 12.8 q 2.8 to 3.5 q 0.3 fM (n=9; mean q SE); p <0.01) after addition of vitamins, but plasma cholesterol did not change (522 q 63 vs. 514 q 41 mg/dL; p >0.05). In response to intraarterial collagen, blood flow to the leg decreased by 30 q 3% and 38 q 5%, respectively, before and after vitamin supplementation (p <0.05). In vivo responses to endothelium-dependent vasodilators (acetylcholine or ADP) were impaired at baseline and did not improve after addition of vitamins. In the carotid artery ex vivo, relaxation to acetylcholine improved only slightly after vitamin supplementation. Ex vivo thrombomodulin anticoagulant activity was 3-fold higher in monkeys fed the atherogenic diet (with or without B vitamins) than in normal monkeys (p <0.05). We conclude that atherosclerosis in monkeys is associated with elevated thrombomodulin activity, and that normalization of plasma H(e) is not sufficient to restore normal vascular function during persistent hypercholesterolemia.