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：血管内皮产生大量的生长因子、细胞因子和生物活性介质关键调节健康和疾病中的血管稳态。在上一个资助期间，我们提供证据表明内皮细胞中转录因子 KLF2 的表达是由以下因素诱导的生物力学刺激，如层流剪切应力 (LSS) 和药理刺激，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）。我们也证明两种刺激对 KLF2 的诱导依赖于 MEF2 的成员转录因子家族。旨在阐明 KLF2 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药物的表达血栓调节蛋白 (TM) 和内皮一氧化氮合酶 (eNOS) 等因子。重要的是，还提供了证据表明层流或他汀类药物诱导 TM 和 eNOS 的能力是 KLF2 依赖。最后，我们的研究表明 KLF2 可以抑制细胞因子介导的亲- 炎症和促血栓形成因子（例如组织因子和纤溶酶原激活剂抑制剂-1）通过其降低 NF?B 活性的能力。与此效果一致，KLF2 过度表达增加凝血时间，而 KLF2 的敲低则缩短了凝血时间。综合起来，这些研究为该更新应用程序提供基础，该应用程序将更详细地探讨 KLF2 的作用。瞄准 1，我们将探索体外和体内流动和他汀类药物介导的 KLF2 诱导的分子基础。在目标 2 中，我们将确定 KLF2 介导的靶基因诱导的分子基础以及 KLF2 缺乏对体内血管血栓形成的功能影响。最后，在目标 3 中，我们将确定 KLF2 介导的促炎靶基因抑制的分子基础以及 KLF2 缺陷对体内动脉粥样硬化血栓形成的功能影响。我们预计这些研究将为 KLF2 在内皮细胞中的作用提供新颖和基本的见解生物学。此外，在他汀类药物的背景下更好地了解 KLF2 功能可能会提供为治疗血管炎症和疾病的新治疗策略奠定了基础血栓性疾病状态。叙述：尽管采取了最大程度的药物治疗，心血管疾病仍然是发病的第一大原因和我们社会的死亡率。因此，显然需要确定新的治疗策略。目前的范式表明，所有血管内壁的血管内皮细胞功能障碍是血管疾病发病机制中的一个关键的早期事件。我们的研究已经确定了遗传因素，可以赋予内皮细胞有利的特性，并由一类诱导称为他汀类药物。我们的努力重点是加深对此的理解因子在内皮细胞中的作用，希望此类研究可以为以下方面提供基础：旨在治疗血管炎症疾病状态的新治疗策略。

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.