Abstract
Objective- Mutations in Krüppel like factor-11 ( KLF11), a gene also known as maturity-onset diabetes mellitus of the young type 7, contribute to the development of diabetes mellitus. 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 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 mice, whereas bone marrow transplantation could not rescue this phenotype, suggesting that vascular KLF11 is critical for inhibition of arterial thrombosis. We further demonstrated that vascular smooth muscle cell-specific Klf11 knockout mice also exhibited significantly reduced occlusion time. The expression of tissue factor (encoded by the F3 gene), a main initiator of the coagulation cascade, was increased in the artery of Klf11 knockout mice, as determined by real-time quantitative polymerase chain reaction and immunofluorescence. Furthermore, vascular smooth muscle cells isolated from Klf11 knockout mouse aortas showed increased tissue factor expression, which was rescued by KLF11 overexpression. In human aortic smooth muscle cells, small interfering RNA-mediated knockdown of KLF11 increased tissue factor expression. Consistent results were observed on 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 vascular smooth muscle cells, constituting a potential molecular target for inhibition of arterial thrombosis.
Highlights
MethodsThe data that support the findings of this study are available from the corresponding author on reasonable request
Our data demonstrate that Krüppel like factor-11 (KLF11) is a novel transcriptional suppressor of F3 in vascular smooth muscle cells, constituting a potential molecular target for inhibition of arterial thrombosis
The primary pathogenic process in arterial thrombosis is the rupture of the atherosclerotic plaque, which promotes platelet recruitment, adhesion, aggregation and activation, and results in thrombus growth.[2]
Summary
The data that support the findings of this study are available from the corresponding author on reasonable request. Conventional Klf[11] knockout mice (Klf[11] KO) and wild-type (WT) mice in the C57BL/6J background were previously described[14] and the knockout was confirmed (Figure I in the online-only Data Supplement). The genotype was determined from mouse tail clippings and a pair of polymerase chain reaction primers flanking the downstream LoxP region (Figure IIIA in the online-only Data Supplement). The inducible smooth muscle cell–specific Klf[11] KO (Sm-Klf[11] KO) mice were generated by cross-breeding Klf11fl/fl mice with Myh11CreERT2 mice (019079, Jackson Laboratory).[17] The primer sequences for mouse genotyping are shown (Table I in the online-only Data Supplement). Fourteen days after tamoxifen or corn oil treatment, the reduction of KLF11 expression in the aorta was confirmed by real-time quantitative polymerase chain reaction and Western blot (Figure IIIB–IIIC in the online-only Data Supplement).
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