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

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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.