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MPO and NO signaling in neointima formation

新内膜形成中的 MPO 和 NO 信号传导

基本信息

批准号：
7631216
负责人：
chunxiang Zhang
金额：
$ 30.3万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7631216
关键词：
Adopted Air Angioplasty Animals Arginine Arteries Atherosclerosis Attention Attenuated Balloon Angioplasty Binding Biological Birth Blood Blood Vessels Carotid Arteries Carotid Artery Injuries Characteristics Chloramines Chloride Ion Chlorides Complex Consumption Coronary Coronary heart disease Data Derivation procedure Dose Esters Event Exhibits Functional disorder Gene Expression Gene Proteins Genes Growth Health Care Costs Hemeproteins Human Hydrogen Peroxide Hyperplasia Hypochlorous Acid In Vitro Incidence Injury Knock-out Knockout Mice Lesion Leukocytes Low-Density Lipoproteins Mediating Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Modification Molecular Molecular Profiling Mus NG-Nitroarginine Methyl Ester Names Nitric Oxide Nitric Oxide Signaling Pathway Oxidative Stress Pathogenesis Pathway interactions Patients Percutaneous Transluminal Coronary Angioplasty Peripheral Peripheral arterial disease Peroxidases Physiological Play Procedures Process Production Protein Isoforms Proteins Rattus Reaction Relative (related person)Reporting Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Source Stents System Testing Time Tissues Vascular remodeling Work base coronary angioplasty design indexing inhibitor/antagonist injured leukocyte mediator macrophage monocyte mutant neointima formation neutrophil novel novel therapeutic intervention overexpression research study response restenosis

项目摘要

Description (provided by applicant): Neointima formation is a key event in both atherosclerosis and restenosis after angioplasty. Although a strong association exists between leukocyte and neointima formation, the molecular mechanisms involved in this process remain unclear. Myeloperoxidase (MPO) is a leukocyte-derived heme protein. Under physiological conditions, MPO catalyzes the reaction between hydrogen peroxide (H2O2) and chloride resulting in the formation of MPO-derived chlorinating products. High levels of MPO and MPO-derived chlorinating products are found in human atherosclerotic and restenotic lesions and that elevated levels of MPO are associated with the presence of coronary heart disease. We have recently shown that MPO has a strong negative effect on nitric oxide (NO) signaling both by direct NO consumption and inhibition of NO formation via its chlorinating products. We have demonstrated that MPO is a transcytosable protein. Vessel bound MPO can remain in the vascular wall for a significant period of time. Interestingly, vessel bound MPO not only can use leukocyte-derived H2O2, but also vascular non-leukocyte-derived H2O2 to inhibit NO signaling and induce endothelial dysfunction. Since NO is a known key regulator of neointima formation, we hypothesize that MPO contributes to neointima formation after angioplasty by diminishing NO signaling. Our preliminary data have shown, for the first time, that overexpression of MPO increases, whereas inhibition of endogenous MPO decreases, neointima formation after angioplasty. Studies in specific aim 1 will further determine the role of MPO on neointima formation in rat carotid arteries after balloon injury. Specific aim 2 will identify the molecular mechanism(s) involved in the MPO-induced effect on neointima formation in rat carotid arteries after balloon injury. Specific aim 3 will determine the effect of MPO deficiency on NO signaling and neointima formation, and the effect of NO signaling deficiency on MPO-induced neointima formation after angioplasty in gene knock-out mice. The current proposal will identify a novel mediator, leukocyte-derived MPO, in neointima formation and its molecular mechanism(s). Blocking the MPO pathway might be a new therapeutic approach to restenosis after balloon angioplasty.

描述（申请人提供）：新生内膜形成是血管成形术后动脉粥样硬化和再狭窄的关键事件。尽管白细胞与新生内膜形成之间存在强烈的关联，但参与这一过程的分子机制尚不清楚。髓过氧化物酶（MPO）是一种白细胞来源的血红素蛋白。在生理条件下，MPO催化过氧化氢（H2O2）与氯化物的反应，生成MPO衍生的氯化产物。在人类动脉粥样硬化和再狭窄病变中发现了高水平的MPO和MPO衍生的氯化产物，并且MPO水平升高与冠心病的存在有关。我们最近的研究表明，MPO通过直接消耗NO和通过其氯化产物抑制NO的形成，对一氧化氮（NO）信号传导有很强的负面影响。我们已经证明MPO是一种可转酶蛋白。血管结合的MPO可以在血管壁上停留很长一段时间。有趣的是，血管结合的MPO不仅可以利用白细胞来源的H2O2，还可以利用血管非白细胞来源的H2O2抑制NO信号，诱导内皮功能障碍。由于NO是已知的新内膜形成的关键调节因子，我们假设MPO通过减少NO信号来促进血管成形术后新内膜的形成。我们的初步数据首次表明，血管成形术后，MPO的过表达增加，而内源性MPO的抑制减少，新内膜形成。具体目的1的研究将进一步确定MPO在大鼠颈动脉球囊损伤后新生内膜形成中的作用。特异性目的2将确定mpo诱导大鼠颈动脉球囊损伤后新内膜形成的分子机制。特异性目的3将确定MPO缺乏对NO信号和新生内膜形成的影响，以及NO信号缺乏对基因敲除小鼠血管成形术后MPO诱导新生内膜形成的影响。目前的建议将确定一种新的介质，白细胞来源的MPO，在新内膜形成及其分子机制。阻断MPO通路可能是球囊血管成形术后再狭窄的新治疗途径。