Angiotensin II, oxidative stress and aneurysm formation

血管紧张素 II、氧化应激和动脉瘤形成

基本信息

批准号：
8215740
负责人：
Neal L Weintraub
金额：
$ 38.86万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-16 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215740
关键词：
Abdominal Aortic Aneurysm Adoptive Transfer Age-Years American Amino Acids Aneurysm Angiotensin II Angiotensins Aorta Atherosclerosis Blood Vessels Cardiovascular Diseases Data Deterioration Development Disease Elastases Elderly Enzymes Experimental Animal Model Experimental Models Genetic Human Hypertension Incidence Inflammation Infusion procedures Lead Leukocytes Mediating Medical Modeling Morbidity - disease rate Mus NADPH Oxidase Oxidative Stress Pathogenesis Pathway interactions Patients Peptide Hydrolases Peroxidases Play Population Process Proteins Reactive Oxygen Species Research Resistance Role Rupture Source Sudden Death Supplementation Taurine Testing Tissues Transgenic Animals Transgenic Organisms inhibitor/antagonist insight macrophage monocyte mortality neutrophil nitration novel oxidant stress prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAA) occur commonly in the elderly population and are a major cause of morbidity and mortality. The mechanisms responsible for aneurysm formation are poorly understood, which has impeded identification of effective medical therapies for this disease. Mounting evidence from studies in human AAA, and in experimental animal models, suggests that oxidative stress plays a key role in the pathogenesis of AAA. While a number of enzymatic pathways are capable of inducing vascular oxidant stress and potentially contributing to AAA, we hypothesis that myeloperoxidase (MPO) is instrumental in this process. MPO is an enzyme expressed primarily in neutrophils (PMNs) and to a lesser extent in monocytes/macrophages, that catalyzes the formation of HOCl, a powerful oxidizing specie, and induces protein nitration. In addition, MPO can be taken up into the blood vessel wall, thus amplifying inflammation, oxidative stress and protease degradation. Using two distinct murine models (elastase-induced and angiotensin II infusion in hyperlipidemic mice), we present data showing that aortic MPO activity and chlorotyrosine expression (a marker of HOCl-mediated oxidative stress) are increased during experimental AAA formation. Our data also suggest a potentially novel role for angiotensin II to exacerbate HOCl-mediated oxidative stress in the blood vessel wall. Moreover, supplementation with taurine, a beta amino acid that reacts with and detoxifies HOCl, prevents AAA formation in these experimental models. To test our hypothesis, we propose three specific aims. In aim 1, we will perform selective immunodepletion and adoptive transfer of PMNs from control or MPO- deficient mice.to test the hypothesis that MPO expression in PMNs contributes to experimental AAA formation in the elastase model. Also, we will immnuodeplete PMNs to determine their role in AAA formation in the angiotensin II infusion model. In aim 2, we will test the hypothesis that genetic deficiency of MPO ameliorates AAA formation in the elastase-induced and angiotensin II infusion models. In aim 3, we will test the hypothesis that transgenic expression of human MPO augments experimental AAA formation. In aims 2 and 3, we will also determine whether angiotensin II upregulates expression and activity of MPO in leukocytes, and whether MPO modulates hypertension and atherosclerosis induced by angiotensin II infusion. Our studies will provide novel insight into mechanisms of AAA formation and linkages between key oxidant stress generating pathways in the pathogenesis of cardiovascular disease. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysms are common in elderly Americans and can lead to progressive enlargement and even rupture of the aorta, the largest blood vessel in the body. Our research suggests that an enzyme known as myeloperoxidase, which is present in white blood cells, contributes to inflammation and tissue damage within the aorta, leading to aneurysm formation. The purpose of our research is to investigate the role of myeloperoxidase in aneurysm formation in experimental animal models, and then to determine whether countermeasures against myeloperoxidase may be effective in treating aneurysms in humans.

描述（由申请人提供）：腹主动脉瘤（AAA）通常发生在老年人群中，是发病率和死亡率的主要原因。造成动脉瘤形成的机制知之甚少，这阻碍了该疾病有效的医疗疗法的鉴定。来自人类AAA的研究和实验动物模型的越来越多的证据表明，氧化应激在AAA的发病机理中起关键作用。尽管许多酶促途径能够诱导血管氧化剂应激并有可能导致AAA，但我们假设骨髓过氧化物酶（MPO）在此过程中具有重要作用。 MPO是一种主要在嗜中性粒细胞（PMN）和单核细胞/巨噬细胞较小程度上表达的酶，可催化HOCL的形成，一种强大的氧化特征，并诱导蛋白质硝基化。另外，可以将MPO吸收到血管壁中，从而扩大炎症，氧化应激和蛋白酶降解。使用两种不同的鼠模型（高脂小鼠中的弹性酶诱导和血管紧张素II输注），我们提出数据表明，在实验AAA形成过程中，主动脉MPO活性和氯曲霉素的表达（HOCL介导的氧化应激的标记）增加了。我们的数据还表明，血管紧张素II的潜在新作用加剧了血管壁中HOCL介导的氧化应激。此外，补充牛磺酸是一种与HOCL反应并解毒的β氨基酸，可防止这些实验模型中的AAA形成。为了检验我们的假设，我们提出了三个具体目标。在AIM 1中，我们将从对照或MPO缺乏小鼠中进行选择性的免疫部门和PMN的过继转移。检验PMN中MPO表达的假设有助于弹性酶模型中的实验AAA形成。此外，我们将InmnuoDeplete PMN确定它们在血管紧张素II输注模型中的AAA形成中的作用。在AIM 2中，我们将检验以下假设：MPO的遗传缺乏可以改善弹性酶诱导的和血管紧张素II输注模型中的AAA形成。在AIM 3中，我们将检验以下假设：人MPO的转基因表达增强了实验AAA的形成。在AIMS 2和3中，我们还将确定血管紧张素II上调白细胞中MPO的表达和活性，以及MPO是否调节血管紧张素II输注引起的高血压和动脉粥样硬化。我们的研究将提供对AAA形成机制的新洞察力，以及在心血管疾病发病机理中产生途径的关键氧化应激之间的联系。公共卫生相关性：腹部主动脉动脉瘤在老年人中很常见，可能导致体内最大的血管的主动脉逐渐扩大甚至破裂。我们的研究表明，一种称为白细胞中的称为骨髓过氧化物酶的酶会导致主动脉内的炎症和组织损伤，从而导致动脉瘤形成。我们研究的目的是研究骨髓过氧化物酶在实验动物模型中的动脉瘤形成中的作用，然后确定针对骨髓氧化酶的对策是否可以有效治疗人类的动脉瘤。