Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway.
Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway.
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DOI：
10.1161/atvbaha.112.300349
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Chen YE
中科院分区：
文献类型：
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作者：
Fan Y;Guo Y;Zhang J;Subramaniam M;Song CZ;Urrutia R;Chen YE
血管内皮细胞(EC)的炎症状态是许多血管疾病的关键。新出现的数据表明，编码幼年型7型成熟型糖尿病(MODY7)的Krüppel样因子-11(KLF11)基因的突变有助于新生儿糖尿病的发展。然而，KLF11在心血管系统中的作用尚不清楚。本研究旨在探讨KLF11在血管内皮细胞炎症中的作用。KLF11在血管内皮细胞中高表达，并受促炎刺激诱导。腺病毒介导的KLF11过表达抑制肿瘤坏死因子-α诱导的黏附分子的表达。此外，siRNA介导的KLF11基因敲除增强了内皮细胞的促炎状态。KLF11抑制肿瘤坏死因子-α和核因子-κB p65过表达诱导的黏附分子启动子活性。在机制上，KLF11通过与p65的物理相互作用有效地抑制了NF-κB信号通路。此外，KLF11基因敲除导致p65与VCAM-1和E-选择素启动子的结合增加。在整个机体水平上，KLF11-/-小鼠在给予脂多糖(LPS)后，白细胞向内皮细胞的募集显著增加。综上所述，我们的数据首次证明KLF11是EC炎症激活的抑制因子，这表明KLF11构成了抑制血管炎症性疾病的新的潜在分子靶点。
Endothelial cell (EC) inflammatory status is critical to many vascular diseases. Emerging data demonstrate that mutations of Krüppel like factor-11 (KLF11), a gene coding maturity-onset diabetes of the young type 7 (MODY7), contribute to the development of neonatal diabetes. However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation. KLF11 is highly expressed in vascular endothelial cells (ECs) and induced by pro-inflammatory stimuli. Adenovirus-mediated KLF11 overexpression inhibits expression of tumor necrosis factors (TNF)-α-induced adhesion molecules. Moreover, siRNA-mediated KLF11 knockdown augments the pro-inflammatory status in ECs. KLF11 inhibits promoter activity of adhesion molecules induced by TNF-α and NF-κB p65 overexpression. Mechanistically, KLF11 potently inhibits NF-κB signaling pathway via physical interaction with p65. Furthermore, KLF11 knockdown results in increased binding of p65 to VCAM-1 and E-selectin promoters. At the whole organism level, KLF11-/- mice exhibit a significant increase in leukocyte recruitment to ECs after lipopolysaccharide (LPS) administration. Taken together, our data demonstrate for the first time that KLF11 is a suppressor of EC inflammatory activation suggesting that KLF11constitutes a novel potential molecular target for inhibition of vascular inflammatory diseases.