Vascular dysfunction and oxidative stress in primary amyloidosis

原发性淀粉样变性的血管功能障碍和氧化应激

基本信息

批准号：
7844940
负责人：
Raymond Quezon Migrino
金额：
$ 14.93万
依托单位：
ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844940
关键词：
Abdomen Acetylcholine Acute Address Adipose tissue Affect Alzheimer&apos s Disease Amyloid Amyloid Neuropathies Amyloid Proteins Amyloid deposition Amyloidosis Animals Antioxidants Arteries Attenuated Autologous Stem Cell Transplantation Biopsy Biopsy Specimen Blood Vessels Bradykinin Cardiac Cardiac Myocytes Cations Cell Culture Techniques Chronic Clinical Colon Coronary Coronary artery Coupling Data Deposition Development Diabetes Mellitus Diffuse Dilator Disease Doxorubicin Endothelium Exposure to Figs - dietary Fluorescence Free Radicals Functional disorder Generations Heart Heart Atrium Heart failure High Density Lipoproteins High Dose Chemotherapy Histologic Human Hydrogen Peroxide Hyperglycemia Hyperlipidemia Hypertension Immunoglobulin Deposition Impairment Injury Investigation Ischemia Kidney Lead Learning Life Light Light-Chain Immunoglobulins Lipid Peroxidation Liver Measures Mediating Microcirculatory Bed Mitochondria Modeling Molecular Conformation Muscle Cells NADPH Oxidase Nature Organ Oxidants Oxidative Stress Papaverine Parkinson Disease Patients Peripheral Peripheral Nerves Phase II Clinical Trials Plasma Cell Neoplasm Play Preparation Primary Systemic Amyloidosis Production Proteins Published Comment Rattus Reactive Oxygen Species Renal function Research Research Personnel Rodent Role Rotenone Source Superoxides Symptoms System Testing Time Tissue Model Tissues Vascular Diseases Vasodilation antioxidant therapy arteriole base cardiovascular injury chemotherapy design gp91ds-tat human tissue hydroethidine immunoglobulin deposition disease information gathering insight mitoquinone multiorgan injury novel novel therapeutics outcome forecast oxidative damage pressure public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Primary systemic amyloidosis is a plasma cell dyscrasia that is often fatal especially if there is cardiac involvement. Untreated, patients with heart failure have median survival of 4-8 months, yet these patients are often ineligible for life-saving high dose chemotherapy and autologous stem cell transplantation. It results from the deposition of misfolded amyloid proteins derived from immunoglobulin light chains and affects the heart, gut, kidneys and peripheral nerves. Biopsy studies and animal studies suggest that amyloid light chains cause oxidative stress leading to tissue damage or dysfunction in colon and cardiac tissues. There is evidence that early endothelial dysfunction precedes onset of amyloid deposition and that amyloid light chains may cause acute tissue injury. Diffuse vascular dysfunction involving small and medium sized arteries may play a central role in causing multiorgan injury. Despite the grim prognosis associated with the disease, however, we know little about the mechanism of injury. Our preliminary results demonstrate impaired endothelial function in human adipose arterioles obtained from non-amyloid subjects following brief exposure to amyloid light chains. This was associated with increased superoxide production. Mitochondria targeted antioxidant treatment preserved endothelial function. We will expand on our initial observations. We plan to test our overall hypothesis that primary amyloid light chains acutely impair endothelial function by increasing reactive oxygen species production in both coronary arterioles and adipose arterioles from subjects without amyloid disease. We further hypothesize that the mitochondria is a source of reactive oxygen species and that antioxidant treatment with mitoquinone, a mitochondria targeted antioxidant will preserve endothelial function. To test these hypotheses, we propose to 1. measure endothelium-dependent and endothelium-independent dilation in isolated human coronary and adipose arterioles (from non-amyloid subjects) before and following exposure to amyloid light chains (obtained from primary amyloidosis subjects); 2. measure reactive oxygen species (superoxide and hydrogen peroxide) in coronary and adipose arterioles following exposure to amyloid light chain and 3. measure the effect of mitoquinone on endothelial function and reactive oxygen species generation in coronary and adipose arterioles following exposure to amyloid light chains. The proposal is novel and significant. It addresses for the first time the mechanism behind vascular injury and endothelial dysfunction in primary amyloidosis. We propose using a human tissue model for the first time in studying this disease that will have more relevant translational application as compared to animal or cell culture studies. We will also test a novel (mitoquinone) antioxidant therapy that may broaden management options for this fatal disease. Understanding the mechanism behind this early injury may allow us to discover new therapeutic strategies to address extensive organ damage in full-blown disease, a model that is seen in other vascular insults such as hyperglycemia, hypertension and hyperlipidemia. The information gathered and the application of the human vascular model may be useful in the study of other amyloid diseases that share common mechanisms of injury, such as Alzheimer's disease or diabetes. PUBLIC HEALTH RELEVANCE: Primary systemic amyloidosis can be a fatal disease and it is caused by the production and deposition of abnormal immunoglobulin light chain proteins in various organs such as the heart, blood vessels, kidneys, gut and liver. The cause of injury to blood vessels by amyloid light chains is unknown. The project will determine if exposure of isolated human blood vessels from discarded tissue to amyloid light chains will impair its function and whether this impairment is caused by oxidative stress. The project will also determine if mitoquinone, a novel antioxidant, will reduce the impairment in function of the blood vessel caused by amyloid light chains. The research will provide important information on the basis and possible treatment of primary systemic amyloidosis that may lead to improvement in survival in these patients.

描述（由申请人提供）：原发性系统性淀粉样变性是一种浆细胞恶液质病，通常是致命的，尤其是当有心脏受累时。如果未经治疗，心力衰竭患者的中位生存期为 4-8 个月，但这些患者往往没有资格接受挽救生命的大剂量化疗和自体干细胞移植。它是由免疫球蛋白轻链衍生的错误折叠淀粉样蛋白沉积引起的，会影响心脏、肠道、肾脏和周围神经。活检研究和动物研究表明，淀粉样蛋白轻链会引起氧化应激，导致结肠和心脏组织的组织损伤或功能障碍。有证据表明，早期内皮功能障碍先于淀粉样蛋白沉积发生，并且淀粉样蛋白轻链可能导致急性组织损伤。涉及中小动脉的弥漫性血管功能障碍可能在引起多器官损伤中发挥核心作用。然而，尽管与该疾病相关的预后很严峻，但我们对损伤机制知之甚少。我们的初步结果表明，在短暂暴露于淀粉样蛋白轻链后，从非淀粉样蛋白受试者获得的人脂肪小动脉的内皮功能受损。这与超氧化物产生增加有关。线粒体靶向抗氧化治疗保留了内皮功能。我们将扩展我们的初步观察。我们计划检验我们的总体假设，即初级淀粉样蛋白轻链通过增加无淀粉样蛋白疾病受试者的冠状小动脉和脂肪小动脉中活性氧的产生来严重损害内皮功能。我们进一步假设线粒体是活性氧的来源，并且用线粒体靶向抗氧化剂线粒体醌进行抗氧化治疗将保留内皮功能。为了检验这些假设，我们建议 1. 在暴露于淀粉样蛋白轻链（从原发性淀粉样变性受试者获得）之前和之后，测量分离的人冠状动脉和脂肪小动脉（来自非淀粉样蛋白受试者）的内皮依赖性和内皮非依赖性扩张； 2. 测量暴露于淀粉样蛋白轻链后冠状动脉和脂肪小动脉中的活性氧（超氧化物和过氧化氢），以及 3. 测量暴露于淀粉样蛋白轻链后米托醌对冠状动脉和脂肪小动脉中内皮功能和活性氧生成的影响。该提案新颖且意义重大。它首次阐述了原发性淀粉样变性中血管损伤和内皮功能障碍背后的机制。我们建议首次使用人体组织模型来研究这种疾病，与动物或细胞培养研究相比，这将具有更相关的转化应用。我们还将测试一种新型（线粒体醌）抗氧化疗法，该疗法可能会扩大这种致命疾病的治疗选择。了解这种早期损伤背后的机制可能使我们能够发现新的治疗策略，以解决成熟疾病中的广泛器官损伤，这种模型在高血糖、高血压和高脂血症等其他血管损伤中也可见到。收集的信息和人体血管模型的应用可能有助于研究具有共同损伤机制的其他淀粉样蛋白疾病，例如阿尔茨海默病或糖尿病。公共卫生相关性：原发性系统性淀粉样变性可能是一种致命性疾病，是由心脏、血管、肾脏、肠道和肝脏等不同器官中异常免疫球蛋白轻链蛋白的产生和沉积引起的。淀粉样蛋白轻链损伤血管的原因尚不清楚。该项目将确定从废弃组织中分离出的人体血管暴露于淀粉样蛋白轻链是否会损害其功能，以及这种损害是否是由氧化应激引起的。该项目还将确定一种新型抗氧化剂米托醌是否会减少淀粉样蛋白轻链引起的血管功能损伤。该研究将为原发性系统性淀粉样变性的基础和可能的治疗提供重要信息，从而可能改善这些患者的生存率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protective role of clusterin in preserving endothelial function in AL amyloidosis.

DOI：
10.1016/j.atherosclerosis.2012.08.028
发表时间：
2012-11
期刊：
ATHEROSCLEROSIS
影响因子：
5.3
作者：
Franco, Daniel A.;Truran, Seth;Burciu, Camelia;Gutterman, David D.;Maltagliati, Anthony;Weissig, Volkmar;Hari, Parameswaran;Migrino, Raymond Q.
通讯作者：
Migrino, Raymond Q.

Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans.

DOI：
10.2337/db14-0976
发表时间：
2015-07
期刊：
Diabetes
影响因子：
7.7
作者：
Koska J;Sands M;Burciu C;D'Souza KM;Raravikar K;Liu J;Truran S;Franco DA;Schwartz EA;Schwenke DC;D'Alessio D;Migrino RQ;Reaven PD
通讯作者：
Reaven PD