Flow Responsive Mediators of Inflammation and Survival

炎症和生存的流量响应介质

基本信息

批准号：
8208041
负责人：
Bradford C Berk
金额：
$ 38.63万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208041
关键词：
Abbreviations Acute Adhesions Adhesives Angioplasty Antioxidants Apolipoprotein E Apoptosis Area Atherosclerosis Binding Biological Availability Blood Vessels Blood flow Bypass Cause of Death Cell Nucleus Cell Survival Cell membrane Cell physiology Cells Cellular Stress Chemotactic Factors Complex Cytoplasm Data Development Disease Endothelial Cells Environment Event Exhibits Extracellular Protein Fluorescence Functional disorder G6PD gene Glucosephosphate Dehydrogenase Goals Human Immunohistochemistry Inflammation Inflammation Mediators Inflammatory Intervention JUN gene Knockout Mice Ligands Location MAP3K5 gene MAPK8 gene Macrophage Activation Mediating Metalloproteases Mitogen-Activated Protein Kinases Mus Myocardial Infarction N-terminal NF-kappa B Natriuretic Peptides Nitric Oxide Nuclear Operative Surgical Procedures Oxidation-Reduction Oxidative Stress PTPN11 gene Pathology Pathway interactions Pattern Phenotype Phosphotransferases Process Production Proliferating Prostaglandins I Protein Binding Protein Deficiency Protein Kinase Protein Tyrosine Phosphatase Proteins Publishing Reactive Oxygen Species Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Role Rupture Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Src homology 2 domain-containing, transforming protein 1 Staging Stroke Superoxide Dismutase Thioredoxin Tumor Necrosis Factor-alpha Tyrosine Phosphorylation Umbilical vein Vascular Cell Adhesion Molecule-1 abstracting atheroprotective base biological adaptation to stress caspase-3 clinically significant cytokine glutaredoxin improved insight macrophage monocyte novel novel strategies novel therapeutic intervention oxidized low density lipoprotein prevent protein expression protein function protein tyrosine phosphatase 1B response scaffold shear stress therapeutic development therapy development

项目摘要

Abstract/Summary Inflammation contributes to development of atherosclerosis. Atherosclerosis is decreased in regions of steady flow associated with high shear stress (termed s-flow), compared to regions of disturbed and low flow (termed d-flow). This finding has yielded the concept that s-flow is atheroprotective and d-flow is atheropromoting, in part by causing endothelial cell (EC) dysfunction. Previously we showed that s-flow activated thioredoxin-1 (Trx1) in EC, decreased expression of the Trx1 interacting protein (Txnip), and inhibited tumor necrosis factor (TNF) signaling. Several findings indicate that Txnip-dependent signaling represents a unique atheropromoting mechanism. 1) Txnip expression is increased by d-flow and promotes the adhesive phenotype of EC, by stimulating VCAM-1 expression. 2) Txnip specifically inhibits Trx1 function and contributes to oxidative stress in EC. 3) Txnip is required for TNF- mediated JNK and caspase-3 activation in EC. 4) Exciting preliminary data show that TNF causes Trx1 and Txnip to translocate to the plasma membrane and stimulate a tyrosine kinase receptor (TKR) signaling pathway that inhibits apoptosis via Akt activation (Fig. 1). Recently, SHP2, a protein tyrosine phosphatase (PTPase), was shown to stimulate the Apoptosis Signal-regulated Kinase (ASK1)-JNK-VCAM1 pathway. 5) Our data show that Txnip binding to SHP2 also activates this pathway (Fig. 1). Thus our major hypothesis is Txnip, like NF-kB, stimulates both pro-survival and pro-inflammatory pathways in EC. In the proposed aims we will identify mechanisms to separate the Txnip-Trx1-TKR-Akt survival pathway from the Txnip-SHP2-ASK1 inflammation pathway. Aim 1: Show that Trx-Txnip stimulates TKR activation and survival by assembling signal complexes and inhibiting PTPases. Aim 2: Show that Txnip regulates SHP2 activity and subcellular location modulating ASK1 activity. Aim 3: Show that d-flow alters Txnip expression and location inhibiting Trx1 activity and activating ASK1. Aim 4: Show that EC-specific Txnip knockout mice exhibit improved EC function and decreased atherosclerosis. These studies should provide insight into mechanisms by which flow inhibits inflammation and facilitate development of therapeutic approaches to limit atherosclerosis.

摘要/总结炎症有助于动脉粥样硬化的发展。动脉粥样硬化在稳定区域减少与受干扰和低流量区域（称为 s 流）相比，与高剪切应力相关的流量（称为 s 流） d-流量）。这一发现得出了 s 流具有动脉粥样硬化保护作用而 d 流具有促进动脉粥样硬化作用的概念。部分是通过引起内皮细胞（EC）功能障碍。之前我们表明 s-flow 激活硫氧还蛋白-1 (Trx1) 在 EC 中，降低 Trx1 相互作用蛋白 (Txnip) 的表达，并抑制肿瘤坏死因子 (TNF) 信号传导。多项研究结果表明，Txnip 依赖性信号传导代表了一种独特的促动脉粥样硬化机制。 1) d-flow 增加 Txnip 表达并促进粘附通过刺激 VCAM-1 表达来改变 EC 表型。 2) Txnip特异性抑制Trx1 功能并有助于 EC 中的氧化应激。 3) TNF-需要Txnip 介导 EC 中 JNK 和 caspase-3 的激活。 4) 令人兴奋的初步数据表明 TNF 导致 Trx1 和 Txnip 易位至质膜并刺激通过 Akt 抑制细胞凋亡的酪氨酸激酶受体 (TKR) 信号通路激活（图1）。最近，SHP2，一种蛋白酪氨酸磷酸酶（PTPase），被显示可刺激细胞凋亡信号调节激酶 (ASK1)-JNK-VCAM1 途径。 5）我们的数据表明，Txnip 与 SHP2 的结合也激活了该通路（图 1）。 1）。因此，我们的主要假设是 Txnip，像 NF-kB 一样，既刺激促生存又刺激 EC 中的促炎途径。在拟议的目标中，我们将确定机制将 Txnip-Trx1-TKR-Akt 生存途径与 Txnip-SHP2-ASK1 分开炎症途径。目标 1：证明 Trx-Txnip 刺激 TKR 激活并通过组装信号复合物和抑制 PTPase 来维持生存。目标 2：证明 Txnip 调节 SHP2 活性和亚细胞位置调节 ASK1 活性。目标 3：证明 d-flow 改变 Txnip 表达并抑制 Trx1 活性并激活 ASK1 的位置。目标 4：证明 EC 特异性 Txnip 敲除小鼠表现出改善 EC 功能并减少动脉粥样硬化。这些研究应该提供对机制的深入了解通过流动抑制炎症并促进治疗方法的开发以限制动脉粥样硬化。