1. KLF11 (Krüppel-Like Factor 11) Modulates Arterial Thrombosis
- Author
-
Clayton S, Lewis and Vladimir Y, Bogdanov
- Subjects
Repressor Proteins ,endocrine system ,Kruppel-Like Transcription Factors ,Humans ,Cell Cycle Proteins ,Thrombosis ,Apoptosis Regulatory Proteins ,Article ,Thromboplastin ,Transcription Factors - Abstract
OBJECTIVE: Mutations in Krüppel like factor-11 (KLF11), a gene also known as maturity-onset diabetes of the young type 7, contribute to the development of diabetes. KLF11 has anti-inflammatory effects in endothelial cells and beneficial effects on stroke. However, the function of KLF11 in the cardiovascular system is not fully unraveled. In this study, we investigated the role of KLF11 in vascular smooth muscle cell (VSMC) biology and arterial thrombosis. APPROACH AND RESULTS: Using a ferric chloride-induced thrombosis model, 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, suggesting that vascular KLF11 is critical for inhibition of arterial thrombosis. We further demonstrated that VSMC specific Klf11 knockout mice also exhibited significantly reduced occlusion time. The expression of tissue factor (TF, encoded by the F3 gene), a main initiator of the coagulation cascade, was increased in the artery of Klf11 KO mice, as determined by real-time quantitative PCR and immunofluorescence. Furthermore, VSMCs isolated from Klf11 KO mouse aortas showed increased TF expression, which was rescued by KLF11 overexpression. 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 F3 at the transcriptional level as determined by reporter and chromatin immunoprecipitation assays. CONCLUSIONS: Our data demonstrate that KLF11 is a novel transcriptional suppressor of F3 in VSMCs, constituting a potential molecular target for inhibition of arterial thrombosis.
- Published
- 2019