KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression

Wenying Liang; Haocheng Lu; Jinjian Sun; Guizhen Zhao; Huilun Wang; Yanhong Guo; Daniel Eitzman; Y Eugene Chen; Yanbo Fan; Jifeng Zhang

doi:10.1055/s-0041-1735191

Thrombosis and Haemostasis, Table of Contents

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

Wenying Liang

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

²Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States

,

Haocheng Lu

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Jinjian Sun

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Guizhen Zhao

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Huilun Wang

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

²Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States

,

Yanhong Guo

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Daniel Eitzman

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Y Eugene Chen

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

,

Yanbo Fan

³Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States

⁴Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States

,

Jifeng Zhang

¹Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States

› Author Affiliations

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.

Keywords

endothelial cells - early growth response protein 1 - Krüppel-like factor - tissue factor - venous thrombosis

Full Text

References

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Supplementary Material

Supplementary Material