flow-Mediated Atheroprotection

血流介导的动脉粥样硬化保护

基本信息

批准号：
7485121
负责人：
Bradford C Berk
金额：
$ 52.52万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7485121
关键词：
4 hydroxynonenal 8-hydroxy-2&apos -deoxyguanosine Abbreviations Adhesions Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Atherosclerosis Binding Blood Vessels Blood flow Bos taurus Cattle Cells Chemotactic Factors Cholecalciferol Data Development Endopeptidases Endothelial Cells Environment Epoprostenol Event Extracellular Matrix Proteins Family Figs - dietary Fluorescence Focal Adhesion Kinase 1 Genes Glucosephosphate Dehydrogenase Glutathione Glutathione Reductase Green Fluorescent Proteins Human Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 JUN gene Laboratories Ligands Low Density Lipoprotein Receptor MAP3K5 gene MAPK14 gene MAPK7 gene MAPK7 gene MEKs Macrophage Activation Mediating Mediator of activation protein Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Modeling Mus N-terminal NADH oxidase NADP Natriuretic Peptides Nitric Oxide Nitric Oxide Synthase Oxidative Stress Oxidoreductase PTK2 gene PTPN11 gene Pathology Peptide Hydrolases Phosphorylation Phosphotransferases Physiological Post-Translational Protein Processing Process Production Proliferating Prostaglandins I Protein Kinase Protein Kinase C Proteins Reactive Oxygen Species Reduced Glutathione Regulation Role Rupture Signal Pathway Signal Transduction Smooth Muscle Myocytes Staging Superoxide Dismutase Thioredoxin Tumor Necrosis Factor-alpha Tumor Necrosis Factors Umbilical vein Vascular Cell Adhesion Molecule-1 activating transcription factor atheroprotective base clinically significant concept cytokine glutaredoxin human TNF protein in vivo inhibitor/antagonist insight macrophage member monocyte novel therapeutics oxidized low density lipoprotein programs protein expression response shear stress stress-activated protein kinase 1 tetrahydrobiopterin tissue culture transcription factor vascular inflammation

项目摘要

Inflammation contributes at each stage in the development of clinically significant atherosclerosis. The initiation and progression of atherosclerosis is decreased in regions of steady flow associated with high laminar shear stress, compared to regions of turbulent and low flow. This finding has yielded the concept that "normal" flow is atheroprotective. Tissue culture and in vivo studies have shown that normal flow decreases oxidative stress by activating antioxidant mechanisms. The major hypothesis of this proposal is that normal flow promotes a reducing environment in endothelial cells that decreases inflammation and limits atherosclerosis. Our laboratory has focused on regulation of the mitogen activated protein kinases (MAPKs) by flow. MAPKs phosphorylate and activate transcription factors that induce expression of both pro- and anti-inflammatory molecules. In particular, apoptosis signal kinase-1 (ASK1) and its downstream effectors, c-Jun N-terminal kinase (JNK) and p38, are activated by almost all inflammatory cytokines. We believe that understanding the mechanisms by which flow regulates activation of ASKl-JNK-p38 will provide insight into the atheroprotective mechanisms induced by flow. We propose a model based on preliminary data that flow stimulates glucose 6-phosphate dehydrogenase (G6PD) which increases NADPH formation. NADPH increases the level of reduced glutathione (GSH) which maintains the key antioxidant molecules glutaredoxin (Grx) and thioredoxin (Trx) in reduced forms. Grx and Trx bind to ASK1 and keep ASK1 inactive. Flow also decreases expression of vitamin D3 upregulated protein (VDUP1) which is an endogenous inhibitor of Trx. To characterize the mechanisms by which flow inhibits ASK1 we will compare the effects of normal flow (shear stress = 12 dyn/cm2) and disturbed flow (low shear stress = 0.4 dyn/cm2 or oscillatory flow) on ASK1 activity basally and in response to tumor necrosis factor-alpha. Four aims are proposed. 1) To characterize the mechanisms by which flow activates G6PD based on mechanosensitive signaling pathways. 2) To determine how Trx inhibits ASK1 function based on the concept that flow maintains Trx in an active state. 3) To show that flow inhibits VDUP1 expression thereby increasing Trx activity and Trx binding to ASK 1. 4) To characterize the role of VDUP1 in atherosclerosis by evaluating the effect of VDUP 1 deficiency on the pathology of the LDL receptor deficient mouse. These studies should provide insight into mechanisms by which flow inhibits arterial inflammation and facilitate development of new therapeutic approaches to limit atherosclerosis.

炎症在临床上显着的动脉粥样硬化发展的每个阶段都有影响。发起和与高层流剪切应力相关的稳定血流区域相比，动脉粥样硬化的进展会减少湍流和低流量区域。这一发现得出了“正常”血流具有动脉粥样硬化保护作用的概念。组织培养和体内研究表明，正常血流通过激活抗氧化机制来减少氧化应激。该提议的主要假设是正常流动促进内皮细胞中的还原环境，从而减少炎症并限制动脉粥样硬化。我们的实验室专注于有丝分裂原激活的调节流式检测蛋白激酶 (MAPK)。 MAPK 磷酸化并激活转录因子，诱导两者表达促炎和抗炎分子。特别是凋亡信号激酶 1 (ASK1) 及其下游效应子 c-Jun N 末端激酶 (JNK) 和 p38 被几乎所有炎症细胞因子激活。我们相信，了解血流调节 ASK1-JNK-p38 激活的机制将提供对动脉粥样硬化保护作用的深入了解流动引起的机制。我们根据流动刺激葡萄糖 6-磷酸的初步数据提出了一个模型脱氢酶 (G6PD) 可增加 NADPH 的形成。 NADPH 增加还原型谷胱甘肽 (GSH) 的水平它保持关键抗氧化剂分子谷氧还蛋白 (Grx) 和硫氧还蛋白 (Trx) 的还原形式。 Grx 和 Trx 与 ASK1 结合并保持 ASK1 不活动。 Flow 还降低了维生素 D3 上调蛋白 (VDUP1) 的表达，该蛋白是 Trx 的内源性抑制剂。为了描述流抑制 ASK1 的机制，我们将比较正常流动（剪切应力 = 12 dyn/cm2）和扰动流动（低剪切应力 = 0.4 dyn/cm2 或振荡流动）的影响影响 ASK1 的基础活性以及对肿瘤坏死因子-α 的反应。提出了四个目标。 1) 表征基于机械敏感信号通路的流动激活 G6PD 的机制。 2) 确定Trx如何基于流维持 Trx 处于活动状态的概念，抑制 ASK1 功能。 3) 证明流动抑制 VDUP1 表达从而增加 Trx 活性以及 Trx 与 ASK 1 的结合。 4) 表征 VDUP1 在通过评估 VDUP 1 缺陷对 LDL 受体缺陷小鼠病理学的影响来研究动脉粥样硬化。这些研究应深入了解血流抑制动脉炎症并促进动脉粥样硬化发展的机制限制动脉粥样硬化的新治疗方法。