KLF4 , the endothelium, and vascular inflammation

描述（由申请人提供）：血管内皮包括与血液的动态界面，并充当生化（例如炎性细胞因子）和生物力学（例如层流剪切应力）刺激的积分器和转换器。刺激内皮细胞， 促炎细胞因子使内皮功能障碍并诱导促粘附和促血栓形成表型。相反，暴露于层流诱导关键基因产物，赋予有效的抗血栓形成，抗粘附和抗炎特性。这些生物化学和生物力学刺激的平衡在生理和病理条件下严格地调节血管功能。KLF 4是Kruppel样锌指转录因子家族的成员， 调节细胞分化和功能等关键过程。我们实验室的研究表明，KLF 4在体外和体内的动脉和静脉内皮细胞（EC）中表达。内皮细胞暴露于促炎刺激或层流剪切应力诱导KLF 4表达。体外功能获得和丧失研究表明：（1）KLF 4抑制了精氨酸诱导的促粘附、促血栓形成因子（如VCAM-1和组织因子（TF））的表达;（2）KLF 4诱导了血流调节因子（如内皮型一氧化氮合酶（eNOS））的表达。 和血栓调节蛋白（TM）。与这些对靶基因的差异作用一致，KLF 4的持续表达抑制免疫细胞粘附到内皮单层并延长凝血时间。基于这些观察结果，我们推测KLF 4可能是内皮细胞功能和血管稳态的关键转录调节因子。本研究将探讨（1）改变KLF 4表达对体外血管内皮细胞激活的分子基础和功能影响，（2）体外血管内皮细胞诱导KLF 4表达的分子基础和改变KLF 4水平对内皮细胞基因表达的功能影响，以及（3）KLF 4过度表达和缺陷对内皮细胞基因表达的影响。 表达和血管功能。本提案中概述的研究结果将提供有关KLF 4在生理和病理状态下EC生物学功能的见解。此外，它们可能为针对广泛的血管炎性疾病状态如动脉粥样硬化的新疗法提供基础。 公共卫生相关性：血管内皮包括与血液的动态界面，并且充当生物化学（例如炎性细胞因子）和生物化学（例如炎性细胞因子）两者的整合器和转换器。 生物力学（例如层流剪切应力）刺激。调节这些不同刺激对血管生物学影响的分子机制仍然知之甚少。这个应用程序探讨了一个名为KLF 4的因子在内皮稳态中的作用。

DESCRIPTION (provided by applicant): The vascular endothelium comprises a dynamic interface with the blood and acts as an integrator and transducer of both biochemical (e.g. inflammatory cytokines) and biomechanical (e.g. laminar shear stress) stimuli. Stimulation of the endothelium with pro-inflammatory cytokines renders the endothelium dysfunctional and induces a proadhesive and pro-thrombotic phenotype. In contrast, exposure to laminar flow induces critical gene products that confer potent anti-thrombotic, anti-adhesive, and anti-inflammatory properties. The balance of these biochemical and biomechanical stimuli critically regulates vascular function under physiologic and pathologic condition. KLF4 is a member of the Kruppel-like family of zinc-finger transcription factors that regulate critical processes such as cellular differentiation and function. Studies in our laboratory demonstrate that KLF4 is expressed in arterial and venous endothelial cells (ECs) in vitro and in vivo. Exposure of endothelial cells to pro-inflammatory stimuli or laminar shear stress induces KLF4 expression. In vitro gain and loss-of-function studies reveal that (1) KLF4 inhibits the cytokine-induced expression of pro-adhesive, prothrombotic factors such VCAM-1 and tissue factor (TF) and (2) KLF4 induces the expression of flow-regulated factors such as endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM). Consistent with these differential effects on target genes, sustained expression of KLF4 inhibits immune cell adhesion to an endothelial monolayer and prolongs blood-clotting time. Based on these observations, we hypothesize that KLF4 may serve as a critical transcriptional regulator of endothelial cell function and vascular homeostasis. The studies outlined in this proposal will explore (1) the molecular basis and functional consequences of altering KLF4 expression on cytokine-mediated EC activation in vitro, (2) the molecular basis for flow-mediated induction of KLF4 and the functional consequences of altering KLF4 levels on endothelial gene expression in vitro, and (3) the effect of KLF4 over expression and deficiency on endothelial gene expression and vessel function in vivo. The results of the studies outlined in this proposal will provide insights regarding KLF4 function in EC biology under physiologic and pathologic states. In addition, they may provide the foundation for novel therapies directed at a broad spectrum of vascular inflammatory disease states such atherosclerosis. PUBLIC HEALTH RELEVANCE: The vascular endothelium comprises a dynamic interface with the blood and acts as an integrator and transducer of both biochemical (e.g. inflammatory cytokines) and biomechanical (e.g. laminar shear stress) stimuli. The molecular mechanisms regulating the effect of these diverse stimuli on vessel biology remain poorly understood. This application explores the role of a factor termed KLF4 in endothelial homeostasis.