flow-Mediated Atheroprotection

血流介导的动脉粥样硬化保护

• 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
• 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' -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

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.

炎症在临床上有意义的动脉粥样硬化发展的各个阶段都有作用。启蒙和启蒙 与高层流切应力相关的稳定流动区域的动脉粥样硬化进展较慢。 湍流和低流区。这一发现产生了“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，正常的血液流动通过激活抗氧化机制来减少氧化应激。 这一建议的主要假设是，正常的血流促进内皮细胞的还原环境， 减少炎症，限制动脉粥样硬化。我们的实验室专注于对激活的有丝分裂原的调节 蛋白激酶(MAPK)由Flow介导。MAPKs磷酸化并激活转录因子，诱导两者的表达 促炎和抗炎分子。尤其是细胞凋亡信号激酶-1(ASK1)及其下游效应因子c-jun N末端激酶(JNK)和p38被几乎所有的炎性细胞因子激活。我们相信，理解 Flow调节Ask1-JNK-p38活化的机制将有助于深入了解动脉粥样硬化的保护作用 流动诱导的机制。我们提出了一个基于初步数据的模型，即流动刺激葡萄糖6-磷酸 脱氢酶(G6PD)，促进NADPH的形成。NADPH增加还原型谷胱甘肽(GSH)水平 它保持关键的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 绑定到ASK1并使ASK1保持非活动状态。FLOW还降低维生素D3上调蛋白(VDUP1)的表达，VDUP1 是TRX的内源性抑制物。为了表征Flow抑制ASK1的机制，我们将比较 正常流(剪应力=12dyn/cm2)和扰流(低剪应力=0.4dyn/cm2或振荡流)的影响 ASK1活性的基础上和对肿瘤坏死因子-α的反应。提出了四个目标。1)描述 Flow激活G6PD的机制基于机械敏感的信号通路。2)确定TRX如何 基于Flow将Trx保持在活动状态的概念，抑制ASK1功能。3)表明心流抑制了 VDUP1的表达，从而增加TRX活性和TRX结合，以ASK 1.4)来表征VDUP1在 通过评估VDUP 1缺乏对低密度脂蛋白受体缺陷小鼠病理的影响来评价动脉粥样硬化。这些 研究应深入了解血流抑制动脉炎症和促进血管病变发展的机制。 限制动脉粥样硬化的新治疗方法。