Wang L, Tran N D, Schreiber S S, Fisher M, Zlokovic B V
Department of Neurosurgery, University of Southern California, School of Medicine, Los Angeles 90033, USA.
Thromb Res. 1998 Dec 1;92(5):213-9. doi: 10.1016/s0049-3848(98)00135-2.
The anticoagulant transmembrane glycoprotein thrombomodulin (TM) is expressed at the luminal surface of vascular endothelial cells. Recently, we showed that TM antigen and TM mRNA are expressed in brain microvessels in several species and that brain capillaries have the capability to activate protein C. The activation of protein C in brain microcirculation was greatly impaired by major stroke risk factors in rats due to downregulation of TM. In this study, a partial sequence of TM was determined from TM mRNA from brain capillaries examined in brain capillaries of the rat, a species that provides a useful model to investigate stroke mechanisms in relation to brain hemostasis. The predicted deduced amino acid sequences for rat TM were compared with other TM sequences. Particularly high homology (77-100%) among functional domains of the protein, i.e., the epidermal growth factor repeats (EGFRs) 1-6 and the transmembrane region, was observed between mice and rats. Somewhat less degree of homology was observed for bovine and human EGFRs 1-6, while the homology of the transmembrane region was 92-96%. All cysteine residues were conserved among the TM sequences, and specific amino acids previously suggested to be essential for activation of protein C by thrombin TM were highly conserved. We conclude that the highly conserved mRNA and protein sequences may reflect a similar anticoagulant role of TM in brain endothelial and systemic vascular endothelial cells across different species.
抗凝跨膜糖蛋白血栓调节蛋白（TM）表达于血管内皮细胞的管腔表面。最近，我们发现TM抗原和TM mRNA在多个物种的脑微血管中均有表达，并且脑毛细血管具有激活蛋白C的能力。在大鼠中，由于TM的下调，主要中风危险因素极大地损害了脑微循环中蛋白C的激活。在本研究中，从大鼠脑毛细血管中检测的TM mRNA确定了TM的部分序列，大鼠是一种用于研究与脑止血相关的中风机制的有用模型。将预测的大鼠TM推导氨基酸序列与其他TM序列进行比较。在蛋白质的功能域，即表皮生长因子重复序列（EGFRs）1-6和跨膜区域之间，小鼠和大鼠之间观察到特别高的同源性（77-100%）。牛和人EGFRs 1-6的同源性程度稍低，而跨膜区域的同源性为92-96%。所有半胱氨酸残基在TM序列中均保守，并且先前认为对凝血酶-TM激活蛋白C至关重要的特定氨基酸高度保守。我们得出结论，高度保守的mRNA和蛋白质序列可能反映了TM在不同物种的脑内皮细胞和全身血管内皮细胞中具有类似的抗凝作用。
