Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14620, USA.
Institute of Medicinal Biotechnology Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Sci Rep. 2017 Jul 27;7(1):6686. doi: 10.1038/s41598-017-06803-x.
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.
转录因子 Kruppel 样因子 2（KLF2）是血管内皮中一种关键的抗炎和抗动脉粥样硬化分子。增强 KLF2 的表达和活性可以改善内皮功能并预防动脉粥样硬化。然而，用于 KLF2 的药理学和分子调节剂却很少。我们使用高通量荧光素酶报告基因检测筛选 KLF2 激活剂，发现单宁酸（TA）是一种多酚化合物，是一种有效的 KLF2 激活剂，可减轻内皮炎症。机制研究表明，TA 通过 ERK5/MEF2 通路诱导 KLF2 的表达。功能上，TA 通过降低黏附分子 VCAM1 的表达，显著减少单核细胞与 ECs 的黏附。利用 Klf2 和 Klf2 小鼠分离的肺 ECs，我们表明 TA 的抗炎作用依赖于 KLF2。总之，我们的结果表明 TA 是一种有效的 KLF2 激活剂，通过上调 KLF2 来减轻内皮炎症。我们的发现为 TA 已确立的有益心血管作用提供了新的机制，并表明 KLF2 可能是动脉粥样硬化性血管疾病的新的治疗靶点。
