Thromb Haemost 2022; 122(05): 777-788
DOI: 10.1055/s-0041-1735191
Endothelium and Angiogenesis

KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression

1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
2   Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
,
Haocheng Lu
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Jinjian Sun
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Guizhen Zhao
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Huilun Wang
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
2   Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
,
Yanhong Guo
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Daniel Eitzman
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Y Eugene Chen
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Yanbo Fan
3   Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
4   Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
,
Jifeng Zhang
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
› Author Affiliations
Funding This work was partially supported by National Institutes of Health grants HL138139 (J.Z.), HL138094 and HL145176 (Y.F.), HL137214 and HL134569 (Y.E.C.), American Heart Association grants 18PRE34000005 (W.L) and 17PRE33400179 (H.L.).

Abstract

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.

Supplementary Material



Publication History

Received: 03 April 2021

Accepted: 20 July 2021

Article published online:
24 August 2021

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