Krüppel-Like Factor-11, a Transcription Factor Involved in Diabetes Mellitus, Suppresses Endothelial Cell Activation via the Nuclear Factor-κB Signaling Pathway

Abstract

Objective 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. Methods and results 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. Conclusions 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.

The Triple-Code Model for Pancreatic Cancer

“…They are modular proteins, which contain small domains that serve as docking platforms for the Sin3-HDAC complex, HATs, WW- and WD40 domain proteins, histone methyltransferases and chromodomain reader molecules [103, 107, 109–112]. In addition, these proteins also heterodimerize with NFκB and PPARγ, which bring additional complexes along for regulatory purposes [102, 113, 114]. For instance, by coupling to the HP1-SUV39H1 as well as to the Sin3-HDAC pathway, these proteins are able to mark the promoters of metabolic gene networks to affect cell survival and growth [101].…”

Role of Krüppel-Like Factor 4 and its Binding Proteins in Vascular Disease

“…Further studies are needed to determine whether a single KLF4 molecule simultaneously exerts multiple effects by forming a combinatorial multi-protein complex, such as KLF4, p53 and p65. In addition, some functions of KLF4 are redundant with those of other KLF family members, including KLF11 78) and KLF15 79) . It is of significant importance to determine whether KLF4 interacts with these KLF family members to exert their overlapping functions.…”

Regulation of an Inflammatory Disease

“…In in vitro scratch assays, overexpression of KLF6 leads to more rapid “wound healing” and enhanced EC migration 45, 46 . KLF11 suppresses NF-κB-mediated EC activation, a role that may be particularly important in diabetes mellitus 47 . Unproven as yet is the ability of KLF6 or KLF11 to alter atherogenesis, although it has been shown that KLF6 levels are upregulated in primary human monocytes after knockdown of the potent anti-inflammatory macrophage transcriptional regulator tristetraprolin 48 .…”