An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1
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 i...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/105253 http://hdl.handle.net/10220/48665 http://dx.doi.org/10.1182/blood-2018-07-864843 |
| _version_ | 1811682228777779200 |
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| author | 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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 |
| author_sort | Pestell, Richard George |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:53:31Z |
| format | Journal Article |
| id | ntu-10356/105253 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:53:31Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1052532019-12-06T21:48:03Z An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 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 Lee Kong Chian School of Medicine (LKCMedicine) Fibrinolysis Hepatocyte-Derived tPA DRNTU::Science::Medicine 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. 2019-06-12T03:59:32Z 2019-12-06T21:48:03Z 2019-06-12T03:59:32Z 2019-12-06T21:48:03Z 2019 Journal Article 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 0006-4971 https://hdl.handle.net/10356/105253 http://hdl.handle.net/10220/48665 http://dx.doi.org/10.1182/blood-2018-07-864843 en Blood © 2019 The American Society of Hematology. All rights reserved. |
| spellingShingle | Fibrinolysis Hepatocyte-Derived tPA DRNTU::Science::Medicine 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 An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title | An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title_full | An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title_fullStr | An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title_full_unstemmed | An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title_short | An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1 |
| title_sort | atf6 tpa pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by dach1 |
| topic | Fibrinolysis Hepatocyte-Derived tPA DRNTU::Science::Medicine |
| url | https://hdl.handle.net/10356/105253 http://hdl.handle.net/10220/48665 http://dx.doi.org/10.1182/blood-2018-07-864843 |
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