Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation
Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation
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DOI：
10.1161/01.atv.0000215638.53414.99
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发表时间：
2006-05-01
影响因子：
8.7
通讯作者：
Jain, MK
中科院分区：
文献类型：
--
作者：
Lin, ZY;Hamik, A;Jain, MK
目的：丝氨酸蛋白酶凝血酶能显著改变内皮细胞基因表达，从而导致促炎表型。最近的研究已经确定Kruppel样因子2（KLF 2）作为内皮基因表达的关键调节因子。在此，我们提供了KLF 2通过改变其主要受体蛋白酶激活受体-1（PAR-1）的表达来抑制凝血酶介导的内皮激活的证据。方法和结果--在人脐静脉内皮细胞中强制表达KLF 2，（组织因子、CD 40 L、纤溶酶原激活物抑制剂-1）、细胞因子/趋化因子（例如，单核细胞趋化蛋白-1、白细胞介素-6 [IL-6]、IL-8）和基质降解酶（例如，基质金属蛋白酶1、2和9）。从机制上讲，KLF 2抑制PAR-1表达，从而抑制凝血酶介导的核因子κ B（NF-κ B）核蓄积和DNA结合。相反，小干扰RNA介导的KLF 2敲低增加PAR-1的表达和凝血酶介导的NF-κ B activation.Conclusion诱导-这些研究确定KLF 2作为一种新的调节PAR-1的表达和凝血酶在内皮细胞中的作用。
Objective - The serine protease thrombin can dramatically alter endothelial gene expression in a manner that confers a proinflammatory phenotype. Recent studies have identified the Kruppel-like factor 2 (KLF2) as a critical regulator of endothelial gene expression. Herein, we provide evidence that KLF2 inhibits thrombin-mediated endothelial activation via alterations in expression of its principal receptor protease-activated receptor-1 (PAR-1).Methods and Results - Forced expression of KLF2 in human umbilical vein endothelial cells potently inhibited the ability of thrombin to induce multiple prothrombotic factors ( tissue factor, CD40L, plasminogen activator inhibitor-1), cytokines/chemokines (eg, monocyte chemotactic protein-1, interleukin-6 [IL-6], IL-8), and matrix degrading enzymes ( eg, matrix metalloproteinases 1, 2, and 9). Mechanistically, KLF2 inhibits PAR-1 expression and, as a consequence, thrombin-mediated nuclear factor kappa B ( NF-kappa B) nuclear accumulation and DNA binding. Conversely, small interfering RNA - mediated knockdown of KLF2 increases PAR-1 expression and thrombin-mediated induction of NF-kappa B activation.Conclusion - These studies identify KLF2 as a novel regulator of PAR-1 expression and thrombin action in endothelial cells.