Hemdahl Anne-Louise, Falk Erling, Thorén Peter, Hansson Göran K
Department of Medicine, Karolinska Institute, SE-171 76, Stockholm, Sweden.
Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H872-7. doi: 10.1152/ajpheart.01083.2003. Epub 2004 Mar 18.
We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE(-/-)) x LDL receptor-deficient (LDLR(-/-)) mice develop myocardial infarction when exposed to hypoxic stress. This study was performed to assess the role of thrombin and thrombosis in this process. ApoE(-/-) x LDLR(-/-) mice were fed a cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while receiving isoflurane anesthesia. One group received a bolus dose (5.6 micromol/kg) of the thrombin inhibitor melagatran, and control animals received PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia followed by normoxia. Ten minutes after the stress, Alzet pumps delivering melagatran (20 nmol x kg x (-1)min(-1)) or PBS were implanted, and the mice were allowed to recover for 48 h. The cardiac response was analyzed by histology, immunohistochemistry, and serum troponin T assay. All animals showed reversible ECG changes as a sign of ischemia during hypoxic stress, and 50% developed infarctions afterward as judged by troponin T levels. The group that received thrombin inhibitor had significantly lower troponin T and smaller myocardial infarctions than the PBS-treated group. These data show that thrombin generation is an important pathogenetic factor and suggest that coronary thrombosis is involved in myocardial infarction in atherosclerotic mice. Exposure of atherosclerotic mice to hypoxia leads to myocardial infarction through a two-phase pathway in which acute transient ischemia is followed by thrombin-dependent, irreversible, myocardial ischemia and myocardial cell death.
我们之前已经表明，动脉粥样硬化的载脂蛋白E缺陷（apoE(-/-)）×低密度脂蛋白受体缺陷（LDLR(-/-)）小鼠在暴露于低氧应激时会发生心肌梗死。本研究旨在评估凝血酶和血栓形成在此过程中的作用。给apoE(-/-)×LDLR(-/-)小鼠喂食富含胆固醇的饮食8个月，然后在接受异氟烷麻醉的同时使其遭受低氧应激。一组在低氧应激前10分钟接受一次推注剂量（5.6微摩尔/千克）的凝血酶抑制剂美拉加群，对照动物接受磷酸盐缓冲液（PBS）。将小鼠暴露于低氧10分钟，随后再进行常氧处理。应激后10分钟，植入输注美拉加群（20纳摩尔×千克×(-1)分钟(-1)）或PBS的Alzet泵，让小鼠恢复48小时。通过组织学、免疫组织化学和血清肌钙蛋白T测定分析心脏反应。所有动物在低氧应激期间均表现出可逆的心电图变化，作为缺血的迹象，并且根据肌钙蛋白T水平判断，50%的动物随后发生梗死。接受凝血酶抑制剂的组的肌钙蛋白T水平显著低于PBS处理组，心肌梗死面积也更小。这些数据表明凝血酶生成是一个重要的致病因素，并提示冠状动脉血栓形成参与了动脉粥样硬化小鼠的心肌梗死。动脉粥样硬化小鼠暴露于低氧会通过一个两阶段途径导致心肌梗死，其中急性短暂性缺血之后是凝血酶依赖性、不可逆的心肌缺血和心肌细胞死亡。
