Early loss of thrombomodulin expression impairs vein graft thromboresistance - Implications for vein graft failure
Early loss of thrombomodulin expression impairs vein graft thromboresistance - Implications for vein graft failure
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DOI：
10.1161/hh0202.105097
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发表时间：
2002-02-08
影响因子：
20.1
通讯作者：
Rade, JJ
中科院分区：
文献类型：
--
作者：
Kim, AY;Walinsky, PL;Rade, JJ
血栓形成是静脉移植物早期失效的主要原因。我们的目的是确定抗凝蛋白、血栓调节蛋白（TM）和内皮细胞蛋白C受体（EPCR）表达的改变是否会损害可能导致静脉移植失败的内皮抗血栓性。自体兔静脉移植物切片的免疫组织化学染色显示，TM的表达，但不是EPCR，移植物植入后早期显着减少。蛋白质印迹分析显示，在植入后的前2周内，TM表达减少>95%，到42天逐渐但不完全恢复。这导致移植物激活蛋白C的能力降低了95%，并与结合凝血酶活性增加有关，在第7天达到峰值28.7 +/- 3.8 mU/cm（2），并保持升高超过14天。使用腺病毒载体介导的基因转移恢复TM表达显著增强了移植物激活蛋白C的能力，并在第7天将结合凝血酶活性降低至与正常静脉相当的水平（分别为5.7 ± 0.4和5.2 ± 1.1 mU/cm（2），P=0.74）。令人惊讶的是，新生内膜形成不受局部凝血酶活性抑制的影响。这些数据表明，TM表达的早期损失显着损害静脉移植物血栓阻力，并导致增强局部凝血酶生成。虽然增强的局部凝血酶生成可能易导致血栓形成导致的早期静脉移植物失败，但似乎不会显著导致新生内膜增生导致的晚期静脉移植物失败。
Thrombosis is the major cause of early vein graft failure. Our aim was to determine whether alterations in the expression of the anticoagulant proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR), impair endothelial thromboresistance that may contribute to vein graft failure. Immunohistochemical staining of autologous rabbit vein graft sections revealed that the expression of TM, but not EPCR, was reduced significantly early after graft implantation. Western blot analysis revealed that TM expression was reduced by >95% during the first 2 weeks after implantation, with gradual but incomplete recovery by 42 days. This resulted in up to a 95% reduction in the capacity of the grafts to activate protein C and was associated with an increase in bound thrombin activity, which peaked on day 7 at 28.7 +/- 3.8 mU/cm(2) and remained elevated for more than 14 days. Restoration of TM expression using adenovirus vector-mediated gene transfer significantly enhanced the capacity of grafts to activate protein C and reduced bound thrombin activity on day 7 to levels comparable to that of normal veins (5.7 +/-0.4 versus 5.2 +/- 1.1 mU/cm(2), respectively, P=0.74). Surprisingly, neointima formation was not affected by this inhibition of local thrombin activity. These data suggest that the early loss of TM expression significantly impairs vein graft thromboresistance and results in enhanced local thrombin generation. Although enhanced local thrombin generation may predispose to early vein graft failure due to thrombosis, it does not seem to contribute significantly to late vein graft failure due to neointimal hyperplasia.