Regulation of Expression of Thrombomodulin on the Cultured Human Umbilical Vein Endothelila Cells and Pathomechanism of Thrombosis

本文研究了凝血酶受体（TR）和血栓调节蛋白（TM）表达的调控机制及其动态变化，调节TR和TM表达的因素，凝血酶激活时TR释放肽（TRRP）测定方法的建立，凝血酶通过TR的信号转导，TM/蛋白C-蛋白S天然抗凝系统的综合评价方法。结果表明：（1）各种刺激均能下调TM的表达，并伴随着TR的增加;（2）氧化低密度脂蛋白和糖基化终产物下调TM的表达，提示这些因素不仅是动脉粥样硬化的危险因素，也是血栓形成的危险因素;（3）成功建立了血清TRRP的测定方法。凝血酶激活TR受体，导致NF-κ B活化，这可能是凝血酶刺激细胞事件的主要途径。5）建立了一种新的体外评价TM/蛋白C和蛋白S天然抗凝系统的方法。我们通过将重组TM加入血浆中来测量凝血酶原酶抑制率。胶原性疾病、心肌梗死、血管炎综合征、脑梗死患者中约有15-30%对rTM抵抗，氧化LDL和糖基化蛋白可能通过TR的增加下调TM，并作为促血栓形成因子发挥作用。因此，凝血酶通过TR的信号转导可能导致增殖和血栓形成。这种血栓前状态部分通过评估TM抗性的TRRP来检测。

We investigated on 1) regulatrory mechanisims of the expression and dynamics of thrombin receptor (TR) and thrombomodulin (TM), 2) factors which regulate the expression of these receptors, 3) establishment of assay method of TR released peptide (TRRP) upon thrombin activation, 4) signal transduction of thrombin through TR,5) total evaluation method of TM/protein C-protein S natural anticoagulant system.As results, we obtained as follows :1) TM is doun-regulated by the stimulation with various stimulus and this is accompanied with increment in TR.2) Oxdized LDL and advanced glycation endoproducts down-regulated the expression of TM suggesting that these factors act as risk factors not only for atherosclerosis but also for thrombosis.3) We succeeded the establishment of assay method of TRRP in serum. This peptide was increased in the serum from diabetes melitus patients with vascular complications.4) Thrombin activates TR receptor and results the activation of NF kappaB.This may be a main pathway in cellular events upon thrombin stimulation.5) We established the new test for evaluation of TM/protein C and protein S natural anticoagulant system in vitro. We measured prothrombinase inhibition rate by recombinat TM added to the plasma. Resistant for rTM was observed about 15-30% patients with collagen diseases, myocardial infarction, vasulitis syndrome, cerebral infarction.Based on these data, oxidized LDL and glycated proteins may down-regulate TM with the increment in TR and act as prothrombotic factors. Thus signal transduction of thrombin through TR may result proliferation and thrombosis. This prothrombotic state is detected in part by the assessment of TRRP of TM resistance.