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

本文从凝血酶受体和血栓调节蛋白的表达和动态调控机制，凝血酶受体和凝血酶调节蛋白表达的调控因素，凝血酶激活时凝血酶释放肽的测定方法的建立，凝血酶通过凝血酶释放肽的信号转导，凝血酶/蛋白C蛋白S天然抗凝系统的总体评价方法等方面进行了研究。结果表明：1)TM受到各种刺激的双重调节，并伴随着TR2的升高。2)氧化低密度脂蛋白和晚期糖基化内皮细胞下调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)我们成功地建立了血清TRRP的检测方法。4)凝血酶激活tr受体，激活核因子kappaB，这可能是凝血酶刺激细胞事件的主要途径。5)我们建立了一种新的体外评价TM/蛋白C和S蛋白天然抗凝系统的方法。通过向血浆中加入重组TM来检测凝血酶原酶抑制率。约15-30%的胶原病、心肌梗死、脉管炎综合征、脑梗塞患者存在RTM耐药现象，提示氧化型低密度脂蛋白和糖化蛋白可能随着tR的增加而下调TM，作为血栓前因子。因此，凝血酶通过受体的信号转导可能导致细胞增殖和血栓形成。这种血栓前状态部分是通过对TM耐药性的TRRP评估来检测的。

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.