Mechanisms of myeloperoxidase and Nox4 interactions in abdominal aortic aneurysm

腹主动脉瘤中髓过氧化物酶和 Nox4 相互作用的机制

基本信息

批准号：
9924277
负责人：
Neal L Weintraub
金额：
$ 52.67万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924277
关键词：
Abdominal Aortic Aneurysm Address Agonist Alleles Aneurysm Angiotensin II Animal Model Aorta Aortic Aneurysm Biological Assay Blood Vessels Calcium Chloride Cell Surface Receptors Cells Cessation of life Coupled Data Deterioration Development Disease Dopamine D2 Receptor Drug Targeting Enzymes Genetic Hematopoietic Heterozygote Human Hydrogen Peroxide In Vitro Inflammation Inflammatory Infusion procedures Knockout Mice Knowledge Leukocytes Link Lipids Lung Mass Spectrum Analysis Mediating Medical Morbidity - disease rate Mus Neutrophil Activation Neutrophil Infiltration Nicotinic Acids Output Oxidants Oxidative Stress Pathogenesis Patients Peroxidases Pharmaceutical Preparations Pharmacology Play Prostaglandin D2 Proteins Receptor Cell Risk Factors Role Rupture Ruptured Aortic Aneurysms Signal Transduction Site Smoking Smooth Muscle Myocytes Source Structure Testing Therapeutic Tissues Treatment Efficacy United States experimental study improved outcome in vivo inhibitor/antagonist macrophage monocyte mortality neutrophil novel overexpression prevent receptor recruit repaired therapy outcome uptake

项目摘要

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) disease is a frequent cause of morbidity and mortality. Roughly 25,000 AAA repairs are performed each year, and AAAs account for over 13,000 deaths annually in the United States. The underlying mechanisms of AAA formation are unknown, which has hampered development of effective medical therapies. Here, we focus on the novel hypothesis that myeloperoxidase (MPO), a leukocyte enzyme expressed primarily in neutrophils (PMNs) that utilizes H2O2 to promote oxidative stress and inflammation, plays a key role in the pathogenesis of AAA. We provide novel preliminary data showing that MPO accrues in the aorta during AAA formation, and that genetic deletion of Nox4, a unique high-output enzymatic producer of H2O2 that is highly expressed in smooth muscle cells (SMCs), blocks MPO uptake and prevents AAA. We further propose that PMN activation/MPO accrual in AAA are regulated by prostaglandin D2 (PGD2) and nicotinic acid (GPR109A) receptors, and that “repurposing” available drugs that target these inflammatory cell receptors is an attractive therapeutic strategy in AAA. Our central hypothesis is that MPO cooperates with Nox4 to promote deleterious oxidative stress in AAA, which can be therapeutically modulated by targeting PGD2 receptors and GPR109A. Three aims are proposed to test our central hypothesis: in Aim1, we will test the hypothesis that Nox4 cooperates with MPO in the pathogenesis of AAA using genetically modified mice and a newly developed mass spectrometry assay that will enable us to determine whether aortic MPO uptake and activity are dependent upon Nox4 during AAA formation. We will also determine whether overexpression of human MPO in hematopoietic cells enhances AAA formation, and if so, whether it can be overcome by SMC Nox4 deletion. In Aim 2, we will test the hypothesis that PGD2 receptors promote PMN/MPO recruitment and MPO-mediated AAA formation using genetically modified mice in which one or both alleles of DP1 or DP2 have been deleted, coupled with and pharmacologic DP receptor agonists and antagonists. In Aim 3, we will test the hypothesis that GPR109A modulates PMN activation and MPO-mediated AAA formation using GPR109A knockout mice coupled with pharmacologic approaches. A particular emphasis of Aims 2 and 3 is to identify promising therapeutic strategies that are both feasible and effective for patients with AAA. This application addresses two significant gaps in the field: i) identifying fundamental mechanisms of AAA formation and ii) using this knowledge to advance medical treatment for patients with AAA.

项目摘要腹主动脉瘤（AAA）疾病通常是发病率和死亡率的原因。每年进行大约25,000个AAA维修，AAAS占13,000多人死亡在美国遇到。 AAA形成的基本机制未知，它具有阻碍了有效的医疗疗法的发展。在这里，我们专注于新的假设髓过氧化物酶（MPO），一种白细胞酶，主要在中性粒细胞（PMN）中表达 H2O2促进氧化应激和炎症，在AAA的发病机理中起关键作用。我们提供新颖的初步数据，显示AAA组中主动脉中的MPO累积，并且 NOX4的遗传缺失，NOX4是H2O2的独特的高输出酶生产商，高度表达平滑肌细胞（SMC）阻止MPO摄取并防止AAA。我们进一步建议PMN AAA中的激活/MPO口音由前列腺素D2（PGD2）和烟酸（GPR109A）调节受体，以及针对这些炎症细胞受体的“重新塑造”可用药物是一种 AAA中有吸引力的治疗策略。我们的中心假设是MPO与NOX4合作促进AAA中有害氧化应激，可以通过热调节靶向PGD2受体和GPR109A。提出了三个目的来检验我们的中心假设： AIM1，我们将检验以下假设：NOX4在使用AAA发病机理中与MPO合作一般修饰的小鼠和新开发的质谱法测定法，这将使我们能够确定主动脉MPO摄取和活性是否取决于AAA形成过程中的NOX4。我们还将确定造血细胞中人类MPO的过表达是否增强了AAA 形成，如果是这样，是否可以通过SMC NOX4删除来克服它。在AIM 2中，我们将测试 PGD2受体促进PMN/MPO募集和MPO介导的AAA形成的假设使用一般修改的小鼠，其中删除了一个或两个等位基因的dp1或两个等位基因，耦合具有和药理学DP受体激动剂和拮抗剂。在AIM 3中，我们将检验假设 GPR109A使用GPR109A敲除调节PMN激活和MPO介导的AAA组小鼠与药物方法结合。目标2和3的特别强调是确定有希望的治疗策略对AAA患者既可行又有效。这应用程序解决了该领域的两个重大差距：i）识别AAA的基本机制组成和ii）使用这些知识来推进AAA患者的医疗。