KLF2 as a regulator of endothelial cell biology

描述（由申请人提供）：血管内皮产生大量生长因子、细胞因子和生物活性介质，这些因子在健康和疾病中关键性地调节血管稳态。在之前的资助期间，我们提供的证据表明，内皮细胞中转录因子KLF 2的表达是由生物力学刺激如层流剪切应力（LSS）和药理学刺激如3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（也称为他汀类药物）诱导的。我们还表明，这两种刺激KLF 2的诱导依赖于MEF 2家族的转录因子的成员。旨在阐明KLF 2在内皮细胞生物学中功能的研究表明，该因子直接调节强效抗炎和抗血栓形成因子（如血栓调节蛋白（TM）和内皮型一氧化氮合酶（eNOS））的表达。重要的是，还提供了层流或他汀类药物诱导TM和eNOS的能力依赖于KLF 2的证据。最后，我们的研究表明，KLF 2可以通过其降低NF κ B活性的能力抑制姜黄素介导的促炎和促血栓形成因子（例如组织因子和纤溶酶原激活物抑制剂-1）的诱导。与这种效应一致，KLF 2过表达增加了凝血时间，而KLF 2敲低减少了凝血时间。总之，这些研究为更详细地探索KLF 2的作用的更新申请提供了基础。在目标1中，我们将探索流动和他汀类药物介导的KLF 2在体外和体内诱导的分子基础。在目标2中，我们将确定KLF 2介导的靶基因诱导的分子基础和KLF 2缺陷对体内血管血栓形成的功能后果。最后，在目标3中，我们将确定KLF 2介导的促炎靶基因抑制的分子基础以及KLF 2缺陷对体内动脉粥样硬化血栓形成的功能后果。我们预计，这些研究将提供有关KLF 2在内皮细胞生物学中的作用的新的和基本的见解。此外，在他汀类药物的背景下，更好地了解KLF 2的功能可能为旨在治疗血管炎症和血栓性疾病状态的新治疗策略提供基础。 项目叙述：尽管有最大限度的药物治疗，心血管疾病仍然是我们社会发病率和死亡率的头号原因。因此，明确需要确定新的治疗策略。目前的范例表明，内衬所有血管的血管内皮细胞的功能障碍是血管疾病发病机制中的关键早期事件。我们的研究已经确定了一种遗传因子，可以赋予内皮细胞有利的特性，并由一类称为他汀类药物诱导。我们的努力集中在开发一个更好的理解这个因素在内皮细胞中的作用，希望这样的调查可能提供的基础，旨在治疗血管炎性疾病状态的新的治疗策略。

DESCRIPTION (provided by applicant): The vascular endothelium produces numerous growth factors, cytokines, and bioactive mediators that critically regulate vascular homeostasis in health and disease. During the previous funding period, we provided evidence that expression of the transcription factor KLF2 in endothelial cells is induced by biomechanical stimuli such as laminar shear stress (LSS) and pharmacologic stimuli such as 3- hydroxyl-3-methyglutaryl coenzyme A reductase inhibitors (also known as statins). We also demonstrated that this induction of KLF2 by both stimuli was dependent on members of the MEF2 family of transcription factors. Studies aimed at elucidating KLF2 function in endothelial cell biology indicate that this factor directly regulates the expression of potent anti-inflammatory and anti-thrombotic factors such as thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS). Importantly, evidence was also provided that the ability of laminar flow or statins to induce TM and eNOS was KLF2 dependent. Finally, our studies demonstrated that KLF2 can inhibit cytokine-mediated induction of pro- inflammatory and pro-thrombotic factors (e.g. tissue factor and plasminogen activator inhibitor-1) through its ability to reduce NFkB activity. Consistent with this effect, KLF2 overexpression increased blood-clotting time while knockdown of KLF2 reduced blood-clotting time. Taken together, these studies provide the basis for this renewal application that will explore the role of KLF2 in greater detail. In Aim 1, we will explore the molecular basis for flow and statin-mediated induction of KLF2 in vitro and in vivo. In Aim 2, we will determine the molecular basis of KLF2 mediated-induction of target genes and the functional consequences of KLF2 deficiency on vascular thrombosis in vivo. And finally, in Aim 3, we will determine the molecular basis of KLF2 mediated-inhibition of proinflammatory target genes and the functional consequences of KLF2-deficiency on atherothrombosis in vivo. We anticipate that these studies will provide novel and fundamental insights regarding the role of KLF2 in endothelial cell biology. Furthermore, a greater understanding of KLF2 function in the context of statins may provide the foundation for novel therapeutic strategies aimed at the treatment of vascular inflammatory and thrombotic disease states. Project Narrative: Despite maximal medical therapy, cardiovascular disease remains the number one cause of morbidity and mortality in our society. As such the identification of novel treatment strategies is clearly required. Current paradigms suggest that dysfunction of the vascular endothelial cell that lines all blood vessels is a critical early event in the pathogenesis of blood vessel diseases. Our studies have identified a genetic factor that can confer favorable properties to endothelial cells and is induced by a class of medications termed statins. Our efforts are focused on developing a greater understanding of this factors role in endothelial cells with the hope that such investigations may provide the foundation for novel therapeutic strategies aimed at the treatment of vascular inflammatory disease states.