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Title: An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1
Authors: Pestell, Richard George
Zheng, Ze
Nayak, Lalitha
Wang, Wei
Wang, Xiaobo
Cai, Bishuang
Lapping, Stephanie
Ozcan, Lale
Ramakrishnan, Rajasekhar
Jain, Mukesh K.
Tabas, Ira
Yurdagul Jr, Arif
Keywords: Fibrinolysis
Hepatocyte-Derived tPA
Issue Date: 2019
Source: Zheng, Z., Nayak, L., Wang, W., Yurdagul Jr, A., Wang, X., Cai, B., . . . Tabas, I. (2019). An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood, 133(7), 743-753. doi:10.1182/blood-2018-07-864843
Series/Report no.: Blood
Abstract: 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 Plat. Hepatocyte-DACH1–knockout mice show increases in liver Plat, circulating tPA, fibrinolytic activity, bleeding time, and time to thrombosis, which are reversed by silencing hepatocyte Plat. Conversely, hepatocyte-ATF6–knockout mice show decreases in these parameters. The inverse correlation between DACH1 and ATF6/PLAT 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.
ISSN: 0006-4971
DOI: 10.1182/blood-2018-07-864843
Rights: © 2019 The American Society of Hematology. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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