Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain.
Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain.
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DOI：
10.3324/haematol.2017.184481
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发表时间：
2018-10
期刊：
影响因子：
10.1
通讯作者：
Ikezoe T
中科院分区：
文献类型：
--
作者：
Wang X;Pan B;Honda G;Wang X;Hashimoto Y;Ohkawara H;Xu K;Zeng L;Ikezoe T
我们以前发现，第五个表皮生长因子样结构域的血栓调节蛋白（TME 5）发挥细胞保护和促血管生成功能，通过G蛋白偶联受体15（GPR 15）。TME 5由三个S-S键组成，将其分为三个环：A（TME 5 A）、B（TME 5 B）和C（TME 5 C）。在此，我们确定了在血管内皮细胞（EC）中产生有利作用的TME 5的最小结构。我们发现，TME 5C，由19个氨基酸组成，而不是TME 5A或TME 5 B，刺激人脐静脉内皮细胞（HUVECs）和人肝窦内皮细胞（HHSECs）的增殖。基质胶塞测定显示TME 5C刺激体内血管生成。此外，TME 5C抵消了钙调磷酸酶介导的HUVEC和HHSEC中的细胞凋亡和血管通透性。蛋白质印迹分析表明，HUVEC或HHSEC暴露于TME 5C增加了与信号转导途径激活相关的抗凋亡髓细胞白血病-1蛋白的水平，包括细胞外信号调节激酶，AKT和促分裂原活化蛋白激酶p38。重要的是，TME 5C在体外不影响凝血途径。TME 5C的细胞保护功能由细胞表面表达的GPR 15介导，因为TME 5C不能保护从Gpr 15敲除（KO）小鼠分离的血管EC。引人注目的是，TME 5C通过抵消窦状隙EC数量的减少成功地改善了鼠模型中的窦状隙阻塞综合征。总之，TM的细胞保护和促血管生成功能在TME 5C中得以保留。使用TME 5C可能是一种有前途的治疗策略，以预防或治疗致命的并发症，如窦阻塞综合征，其发病机制是基于内皮损伤。
We previously found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) exerts cytoprotective and pro-angiogenic functions via G-protein coupled receptor 15 (GPR15). TME5 is comprised of three S-S bonds that divide it into three loops: A (TME5A), B (TME5B), and C (TME5C). Herein we identified the minimum structure of TME5 that produces favorable effects in vascular endothelial cells (ECs). We found that TME5C, composed of 19 amino acids, but not TME5A or TME5B, stimulated the proliferation of human umbilical vein endothelial cells (HUVECs) and human hepatic sinusoidal endothelial cells (HHSECs). Matrigel plug assays showed that TME5C stimulates in vivo angiogenesis. In addition, TME5C counteracted calcineurin inhibitor-induced apoptosis and vascular permeability in HUVECs and HHSECs. Western blot analysis indicated that exposure of either HUVECs or HHSECs to TME5C increased the levels of anti-apoptotic myeloid cell leukemia-1 protein in association with the activation of signal transduction pathways, including extracellular signal-regulated kinase, AKT, and mitogen-activated protein kinase p38. Importantly, TME5C did not affect the coagulation pathway in vitro. The cytoprotective function of TME5C was mediated by cell surface-expressed GPR15, as TME5C was not able to protect vascular ECs isolated from Gpr15 knock-out (KO) mice. Strikingly, TME5C successfully ameliorated sinusoidal obstruction syndrome in a murine model by counteracting the reduction of sinusoidal EC numbers. Taken together, the cytoprotective and pro-angiogenetic functions of TM are preserved in TME5C. The use of TME5C may be a promising treatment strategy to prevent or treat lethal complications, such as sinusoidal obstruction syndrome, whose pathogenesis is based on endothelial insults.
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