Hirokawa K, Aoki N
First Department of Medicine, Tokyo Medical and Dental University.
J Biochem. 1990 Nov;108(5):839-45. doi: 10.1093/oxfordjournals.jbchem.a123290.
Previous studies have shown that thrombomodulin (TM) on endothelial cells is down-regulated by endotoxin, interleukin-1 beta (IL-1 beta), and tumor necrosis factor (TNF). This loss of anti-coagulant potential is thought to be related to the hypercoagulable state in sepsis, inflammation, and cancer. The current studies describe up-regulation of TM in human umbilical vein endothelial cells (HUVECs) by several compounds as judged by increased surface cofactor activity, surface TM antigen, and TM mRNA levels. Surface TM activity was increased by active phorbol esters (10(-8) M, 24-48 h), analogs of cAMP (1-10 mM, 4 h), and forskolin (10(-5) M, 24-48 h). Up-regulation of TM in HUVECs by 4 beta-phorbol 12-myristate 13-acetate (PMA) and dibutyryl cAMP (dBcAMP) was due to de novo synthesis of TM protein resulting from increased TM mRNA levels. The results suggest that protein kinase C and protein kinase A may be involved in cellular regulatory mechanisms for TM expression. In addition, PMA effects on surface TM activity are biphasic, with an initial reduction followed by a significant enhancement. Hence, we propose that compounds capable of increasing intracellular cAMP concentrations in HUVECs may be useful in preventing thrombosis by increasing the anti-thrombotic properties of endothelial cells.
先前的研究表明，内皮细胞上的血栓调节蛋白（TM）会被内毒素、白细胞介素-1β（IL-1β）和肿瘤坏死因子（TNF）下调。这种抗凝潜力的丧失被认为与败血症、炎症和癌症中的高凝状态有关。目前的研究描述了几种化合物可使人类脐静脉内皮细胞（HUVECs）中的TM上调，这是通过表面辅因子活性增加、表面TM抗原和TM mRNA水平来判断的。活性佛波酯（10⁻⁸ M，24 - 48小时）、cAMP类似物（1 - 10 mM，4小时）和福斯高林（10⁻⁵ M，24 - 48小时）可增加表面TM活性。4β-佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）和二丁酰cAMP（dBcAMP）使HUVECs中的TM上调是由于TM mRNA水平增加导致TM蛋白的从头合成。结果表明蛋白激酶C和蛋白激酶A可能参与了TM表达的细胞调节机制。此外，PMA对表面TM活性的影响是双相的，最初会降低，随后会显著增强。因此，我们提出能够增加HUVECs细胞内cAMP浓度的化合物可能有助于通过增强内皮细胞的抗血栓特性来预防血栓形成。
