Department of Medicine, Columbia University Medical Center, New York, NY.
Division of Hematology and Oncology and.
Blood. 2019 Feb 14;133(7):743-753. doi: 10.1182/blood-2018-07-864843. Epub 2018 Dec 1.
Tissue-type plasminogen activator (tPA) is a major mediator of fibrinolysis and, thereby, prevents excessive coagulation without compromising hemostasis. Studies on tPA regulation have focused on its acute local release by vascular cells in response to injury or other stimuli. However, very little is known about sources, regulation, and fibrinolytic function of noninjury-induced systemic plasma tPA. We explore the role and regulation of hepatocyte-derived tPA as a source of basal plasma tPA activity and as a contributor to fibrinolysis after vascular injury. We show that hepatocyte tPA is downregulated by a pathway in which the corepressor DACH1 represses ATF6, which is an inducer of the tPA gene Hepatocyte-DACH1-knockout mice show increases in liver , circulating tPA, fibrinolytic activity, bleeding time, and time to thrombosis, which are reversed by silencing hepatocyte Conversely, hepatocyte-ATF6-knockout mice show decreases in these parameters. The inverse correlation between DACH1 and / is conserved in human liver. These findings reveal a regulated pathway in hepatocytes that contributes to basal circulating levels of tPA and to fibrinolysis after vascular injury.
组织型纤溶酶原激活物（tPA）是纤维蛋白溶解的主要介质，可防止过度凝血而不影响止血。tPA 调节的研究集中于血管细胞在受到损伤或其他刺激时对其进行的急性局部释放。然而，对于非损伤诱导的系统血浆 tPA 的来源、调节和纤溶功能知之甚少。我们探讨了肝细胞来源的 tPA 作为基础血浆 tPA 活性来源的作用和调节，以及作为血管损伤后纤溶的贡献者。我们发现，肝细胞 tPA 的下调途径是通过核心抑制因子 DACH1 抑制 ATF6，ATF6 是 tPA 基因的诱导剂。肝细胞-DACH1 敲除小鼠的肝脏、循环 tPA、纤溶活性、出血时间和血栓形成时间增加，通过沉默肝细胞可逆转这些变化。相反，肝细胞-ATF6 敲除小鼠的这些参数减少。DACH1 和 / 的负相关在人类肝脏中是保守的。这些发现揭示了肝细胞中的一个调节途径，该途径有助于基础循环 tPA 水平和血管损伤后的纤溶。
