The Role of Kruppel-like Factor 11 in Vascular Homeostasis
dc.contributor.author | Liang, Wenying | |
dc.date.accessioned | 2021-09-24T19:06:18Z | |
dc.date.available | 2023-09-01 | |
dc.date.available | 2021-09-24T19:06:18Z | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/169689 | |
dc.description.abstract | Krüppel-like factors (KLFs) are transcription factors containing three conserved zinc finger motifs in the carboxy-terminus and have shown associations with many diseases, including cancer, diabetes, and vascular disorders. Krüppel-like factor 11 (KLF11), originally identified as the causative gene for maturity-onset diabetes of the young type 7 (MODY7), has been reported to facilitate insulin transcription in pancreatic β cells. Previous studies have found that endothelial KLF11 has a protective effect in sepsis, ischemic stroke, and abdominal aortic aneurysm. Considering the common vascular complications in diabetes patients, in this project, we aim to study further the role of KLF11 in vascular homeostasis, especially thrombosis. We applied a ferric chloride-induced thrombosis model to investigate the role of KLF11 in arterial thrombosis. We found that the occlusion time was significantly reduced in conventional Klf11 knockout (Klf11 KO) mice, while bone marrow transplantation could not rescue this phenotype. Given the increased expression of tissue factor (TF; encoded by the F3 gene) in the tunica media of aorta in Klf11 KO mice, we further applied the arterial thrombosis model in vascular smooth muscle cell (VSMC) specific Klf11 knockout mice and found a significant reduction of occlusion time. In human aortic smooth muscle cells, siRNA-mediated knockdown of KLF11 increased TF expression. Consistent results were observed upon adenovirus-mediated overexpression of KLF11. Mechanistically, KLF11 downregulates TF gene expression at the transcriptional level as determined by reporter and chromatin immunoprecipitation assays. In sum, our data demonstrate that KLF11 is a novel transcriptional suppressor of the TF gene in VSMCs, constituting a potential molecular target for inhibition of arterial thrombosis. To study the role of KLF11 in venous thrombosis, we utilized a stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs). We identified an increase in 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-alpha (TNF-α) induced TF expression. 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 the TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 KO mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against DVT, constituting a potential molecular target for treating thrombosis. In summary, KLF11 inhibits the basal TF expression in VSMCs and interrupts the induced EGR1 binding to the TF gene promoter under prothrombotic conditions. Thus KLF11 is important in maintaining vascular homeostasis and can be a promising therapeutic target for preventing or treating arterial thrombosis and DVT. | |
dc.language.iso | en_US | |
dc.subject | Arterial thrombosis | |
dc.subject | Krüppel-like factors | |
dc.subject | Tissue factor | |
dc.subject | Transcription factor | |
dc.subject | Deep vein thrombosis | |
dc.title | The Role of Kruppel-like Factor 11 in Vascular Homeostasis | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Molecular and Integrative Physiology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Chen, Yuqing | |
dc.contributor.committeemember | Holinstat, Michael Allan | |
dc.contributor.committeemember | Eitzman, Daniel T | |
dc.contributor.committeemember | Lin, Jiandie | |
dc.contributor.committeemember | Mortensen, Richard M | |
dc.subject.hlbsecondlevel | Internal Medicine and Specialties | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/169689/1/wenyingl_1.pdf | |
dc.identifier.doi | https://dx.doi.org/10.7302/2734 | |
dc.identifier.orcid | 0000-0001-9985-6674 | |
dc.identifier.name-orcid | Liang, Wenying; 0000-0001-9985-6674 | en_US |
dc.working.doi | 10.7302/2734 | en |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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