Abstract
The transcription factor Kruppel-like factor 2 (KLF2) is a critical anti-inflammatory and anti-atherogenic molecule in vascular endothelium. Enhancing KLF2 expression and activity improves endothelial function and prevents atherosclerosis. However, the pharmacological and molecular regulators for KLF2 are scarce. Using high-throughput luciferase reporter assay to screen for KLF2 activators, we have identified tannic acid (TA), a polyphenolic compound, as a potent KLF2 activator that attenuates endothelial inflammation. Mechanistic studies suggested that TA induced KLF2 expression in part through the ERK5/MEF2 pathway. Functionally, TA markedly decreased monocyte adhesion to ECs by reducing expression of adhesion molecule VCAM1. Using lung ECs isolated from Klf2+/+ and Klf2+/− mice, we showed that the anti-inflammatory effect of TA is dependent on KLF2. Collectively, our results demonstrate that TA is a potent KLF2 activator and TA attenuated endothelial inflammation through upregulation of KLF2. Our findings provide a novel mechanism for the well-established beneficial cardiovascular effects of TA and suggest that KLF2 could be a novel therapeutic target for atherosclerotic vascular disease.
Highlights
Kruppel-like factors (KLFs) are members of the zinc-finger transcription factors family that are critical in the regulation of cell proliferation, differentiation and inflammation[1, 2]
Among the positive hit compounds, we observed that tannic acid (TA) significantly increased Kruppel-like factor 2 (KLF2) promoter luciferase activity at 5 μM
The central finding of this study is that TA induces KLF2 expression and attenuates TNFα-induced inflammation and monocyte cell adhesion in endothelial cells
Summary
Kruppel-like factors (KLFs) are members of the zinc-finger transcription factors family that are critical in the regulation of cell proliferation, differentiation and inflammation[1, 2]. In vivo animal experiments demonstrated that endothelial cell-specific deficiency of KLF2 predisposed to atherosclerosis development[17]. Myeloid-specific Klf[2] knockout in an atheroprone LDL receptor-deficient background (Ldl−/−) increased atherosclerosis progression[18]. Based on these studies, modulating KLF2 expression or function could be a novel strategy for the prevention and treatment of inflammatory related disease including atherosclerosis[2, 6, 9]. COS-7 cells (ATCC, Rockville, MD) were cultured in DMEM (Corning, Cellgro , USA) containing 10% fetal bovine serum (FBS) (Gibco). KLF2 -221 plasmid contains MEF2 binding site while in KLF2 -221 mutant plasmid, the MEF2 binding site was mutated
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