Angiotensin II, oxidative stress and aneurysm formation

血管紧张素 II、氧化应激和动脉瘤形成

• 批准号: 8416977
• 负责人: Neal L Weintraub
• 金额: $ 17.81万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-16 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416977
• 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

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.

描述（由申请方提供）：腹主动脉瘤（AAA）常见于老年人群，是发病率和死亡率的主要原因。对动脉瘤形成的机制知之甚少，这阻碍了对这种疾病的有效药物治疗的确定。来自人类AAA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的发病机制中起着关键作用。虽然许多酶途径能够诱导血管氧化应激并可能导致AAA，但我们假设髓过氧化物酶（MPO）在此过程中起作用。MPO是一种主要在中性粒细胞（PMN）中表达的酶，在单核细胞/巨噬细胞中表达的程度较低，其催化HOCl（一种强氧化物质）的形成并诱导蛋白质硝化。此外，MPO可以被吸收到血管壁中，从而放大炎症、氧化应激和蛋白酶降解。使用两种不同的小鼠模型（弹性蛋白酶诱导和血管紧张素II输注高血压小鼠），我们目前的数据显示，主动脉MPO活性和氯酪氨酸表达（HOCl介导的氧化应激的标志物）增加在实验AAA的形成。我们的数据还表明，血管紧张素II的一个潜在的新的作用，加剧HOCl介导的氧化应激在血管壁。此外，补充牛磺酸（一种与HOCl反应并解毒的β氨基酸）可以防止这些实验模型中AAA的形成。为了验证我们的假设，我们提出了三个具体目标。在目标1中，我们将从对照或MPO缺陷型中进行选择性免疫耗竭和过继转移mice.to检验PMN中MPO表达有助于弹性蛋白酶模型中实验性AAA形成的假设。此外，我们将免疫耗竭中性粒细胞，以确定其在血管紧张素II输注模型中AAA形成中的作用。在目标2中，我们将检验MPO遗传缺陷改善弹性蛋白酶诱导和血管紧张素II输注模型中AAA形成的假设。在目标3中，我们将检验人MPO转基因表达增强实验性AAA形成的假设。在目标2和3中，我们还将确定血管紧张素II是否上调白细胞中MPO的表达和活性，以及MPO是否调节血管紧张素II输注诱导的高血压和动脉粥样硬化。我们的研究将为AAA形成机制和心血管疾病发病机制中关键氧化应激产生途径之间的联系提供新的见解。