KLF2 as a regulator of endothelial cell biology

KLF2 作为内皮细胞生物学的调节剂

基本信息

批准号：
8300954
负责人：
MUKESH Kumar JAIN
金额：
$ 38.86万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300954
关键词：
Adhesives Anti-Inflammatory Agents Anti-inflammatory Binding Biochemical Biological Biomechanics Blood Clot Blood Vessels Blood coagulation Cell Line Cellular biology Coenzyme A Disease Endothelial Cells Endothelium Event Exposure to Family Foundations Functional disorder Funding Gene Expression Gene Targeting Genetic Grant Growth Factor Health Homeostasis Hydroxyl Radical In Vitro Inflammatory Investigation Mediating Mediator of activation protein Medical Molecular Morbidity - disease rate Oxidoreductase Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Plasminogen Activator Inhibitor 1 Property Regulation Research Role Societies Stimulus Thrombomodulin Thromboplastin Thrombosis Time Vascular Endothelial Cell Vascular Endothelium abstracting atherothrombosis base cardiovascular disorder therapy cytokine gene function human NOS3 protein in vivo inhibitor/antagonist insight member mortality novel novel therapeutics overexpression promoter shear stress transcription factor treatment strategy

项目摘要

Abstract: 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 NF?B 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. 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.

抽象的：血管内皮会产生许多生长因子，细胞因子和生物活性介质，这些因子和生物活性介质。严重调节健康和疾病中的血管稳态。在上一个资金期间，我们提供的证据表明，内皮细胞中转录因子KLF2的表达是由生物力学刺激，例如层状剪切应力（LSS）和药理学刺激，例如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）。我们也是证明了两种刺激对KLF2的诱导取决于MEF2成员转录因子家族。旨在阐明内皮细胞生物学中KLF2功能的研究表明该因素直接调节有效的抗炎和抗脉动的表达诸如血小板结合蛋白（TM）和内皮一氧化氮合酶（ENOS）等因素。重要的是，还提供了层流或他汀类药物诱导TM和ENOS的能力为KLF2 依赖。最后，我们的研究表明，KLF2可以抑制细胞因子介导的促进炎症和促脉症因子（例如组织因子和纤溶酶原激活物抑制剂1）通过其减少NF？B活动的能力。与这种效果一致，KLF2过表达增加敲击KLF2的血液封闭时间减少了血液闭合时间。总之，这些研究为这种续签应用提供基础，该应用将更详细地探讨KLF2的作用。目标 1，我们将探索在体外和体内的流动和他汀类药物介导的诱导的分子基础。在AIM 2中，我们将确定靶基因的KLF2介导的诱导的分子基础 KLF2缺乏对体内血管血栓形成的功能后果。最后，在AIM 3中，我们将确定KLF2介导的促炎靶基因的抑制作用的分子基础和 KLF2缺乏对体内动脉粥样硬化的功能后果。我们预计这些研究将提供有关KLF2在内皮细胞中作用的新颖和基本见解生物学。此外，在他汀类药物的背景下，对KLF2功能有更深入的了解新型治疗策略的基础，旨在治疗血管炎症和血栓疾病状态。叙述：尽管医疗疗法最大，但心血管疾病仍然是发病率的第一名和我们社会的死亡率。因此，显然需要确定新型治疗策略。当前的范式表明血管所有血管的血管内皮细胞功能障碍是血管疾病发病机理中的关键早期事件。我们的研究已经确定了遗传因素可以赋予内皮细胞的有利特性，并由一类药物称为他汀类药物。我们的努力专注于对此有更深入的了解因素在内皮细胞中的作用，希望这种调查可以为旨在治疗血管炎性疾病状态的新型治疗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells--brief report.

DOI：
10.1161/atvbaha.112.300317
发表时间：
2012-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
McLean DL;Kim J;Kang Y;Shi H;Atkins GB;Jain MK;Chun HJ
通讯作者：
Chun HJ

Endothelial Grb2-associated binder 1 is crucial for postnatal angiogenesis.

DOI：
10.1161/atvbaha.111.224493
发表时间：
2011-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Zhao J;Wang W;Ha CH;Kim JY;Wong C;Redmond EM;Hamik A;Jain MK;Feng GS;Jin ZG
通讯作者：
Jin ZG

MiRrored regulation of KLF2 and KLF4.

DOI：
10.1161/atvbaha.112.245563
发表时间：
2012-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Hamik A;Jain MK
通讯作者：
Jain MK

Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report.

DOI：
10.1161/atvbaha.112.300471
发表时间：
2012-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Sharma N;Lu Y;Zhou G;Liao X;Kapil P;Anand P;Mahabeleshwar GH;Stamler JS;Jain MK
通讯作者：
Jain MK

Regulation of an inflammatory disease: Krüppel-like factors and atherosclerosis.