Xanthine Oxidase and Bioenergetic Function in Volume Overload

黄嘌呤氧化酶和容量超负荷时的生物能功能

• 批准号: 8059630
• 负责人: Louis J. Dell'Italia
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059630
• 关键词: Acute; Address; Allopurinol; Animal Model; Animals; Attenuated; Basic Science; Bioenergetics; Cardiac Myocytes; Cardiovascular Pathology; Cells; Characteristics; Chronic; Clinical Research; Clinical Trials; Data; Defect; Dimensions; Etiology; Failure; Fistula; Functional disorder; Generations; Genus Hippocampus; Heart; Heart failure; Hour; Human; Ischemia; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Link; Matrix Metalloproteinases; Measurement; Mediating; Medical; Mitochondria; Mitochondrial Proteins; Mitral Valve Insufficiency; Modeling; Modification; Myocardial; Nitrogen; Oxidants; Oxidative Stress; Oxygen; Oxygen Consumption; Oxypurinol; Patients; Pharmacotherapy; Physiologic intraventricular pressure; Principal Investigator; Process; Proteins; Proteomics; Protons; Rattus; Reperfusion Therapy; Role; Source; Staging; Stress; Stretching; Techniques; Testing; Therapeutic; Time; Translating; Ventricular; Working stroke; Xanthine Dehydrogenase; Xanthine Oxidase; clinically relevant; extracellular; gene therapy; hemodynamics; improved; in vivo; insight; mitochondrial dysfunction; mortality; novel; novel therapeutic intervention; oxidative damage; pressure; prevent; public health relevance; repaired; research study; respiratory; response; restoration; xanthine oxidase inhibitor

DESCRIPTION (provided by applicant): Volume overload (VO) in the heart promotes bioenergetic, structural, and functional changes that lead to heart failure. However, the mechanisms of myocardial decompensation and the resulting progression to failure due to VO remain unclear. It is established that VO increases xanthine oxidase (XO) and reactive oxygen and nitrogen species (ROS/RNS). In this proposal we will integrate two critical basic research findings in the context of cardiac failure due to VO: 1) XO as a source of oxidative damage in the heart due to VO and 2) the central role mitochondrial dysfunction in the etiology of VO-mediated heart failure. This concept will be tested through pursuit of the following specific aims in targeted animal and human studies. Aim 1 will test the hypothesis that increased XO activity in VO causes LV dysfunction through cardiomyocyte mitochondrial dysfunction in chronic VO in rat. Aim 2 will test the hypothesis that cardiomyocyte-derived XO activity is responsible for cardiomyocyte MMP activation and mitochondrial dysfunction using gene therapy to knockdown XDH in acute and chronic VO in rats. Aim 3 will test the hypothesis that XO inhibition reduces cardiomyocyte oxidative stress and mitochondrial dysfunction and improves LV function after closure of chronic ACF in rat. These experiments will utilize novel gene therapy techniques in rats to prove cause and effect of XO in cardiomyocytes. Studies of cardiomyocyte mitochondrial function will be performed using Seahorse XF24 in animal cells. The animal and cardiomyocyte studies proposed will determine whether increased XO is a key regulator of oxidative stress and mitochondrial dysfunction in the chronic stretch of a pure VO. These studies, if positive, could provide the scientific impetus for a clinical trial of XO inhibition in patients with isolated VO. PUBLIC HEALTH RELEVANCE: Mechanisms of left ventricular dysfunction in models of volume overload are not well understood and there is currently no recommended medical therapy. Using targeted studies in a clinically relevant animal model the principal investigator addresses the novel hypothesis that cardiomyocyte-derived xanthine oxidase mediates oxidative damage of mitochondria and left ventricular dysfunction in volume overload. These studies in animals, if positive, could provide the scientific impetus for a clinical trial of xanthine oxidase inhibition in patients with isolated volume overload.

描述（由申请人提供）：心脏容量超负荷（VO）会促进生物能、结构和功能的变化，从而导致心力衰竭。然而，心肌失代偿以及由此导致的 VO 导致的衰竭的机制仍不清楚。已确定 VO 会增加黄嘌呤氧化酶 (XO) 以及活性氧和氮 (ROS/RNS)。在本提案中，我们将整合 VO 引起的心力衰竭方面的两项关键基础研究发现：1）XO 作为 VO 引起的心脏氧化损伤的来源；2）线粒体功能障碍在 VO 病因学中的核心作用介导的心力衰竭。这一概念将通过在有针对性的动物和人类研究中追求以下具体目标来进行检验。目标 1 将检验以下假设：VO 中 XO 活性增加通过大鼠慢性 VO 中心肌细胞线粒体功能障碍导致 LV 功能障碍。目标 2 将使用基因疗法敲低大鼠急性和慢性 VO 中的 XDH，检验心肌细胞衍生的 XO 活性导致心肌细胞 MMP 激活和线粒体功能障碍的假设。目标 3 将检验以下假设：XO 抑制可减少大鼠慢性 ACF 闭合后心肌细胞氧化应激和线粒体功能障碍，并改善左心室功能。这些实验将在大鼠中利用新型基因治疗技术来证明 XO 对心肌细胞的因果关系。将使用 Seahorse XF24 在动物细胞中进行心肌细胞线粒体功能的研究。拟议的动物和心肌细胞研究将确定增加的 XO 是否是纯 VO 慢性拉伸中氧化应激和线粒体功能障碍的关键调节剂。这些研究如果是积极的，可以为孤立性 VO 患者的 XO 抑制临床试验提供科学动力。 公共卫生相关性：容量超负荷模型中左心室功能障碍的机制尚不清楚，目前没有推荐的药物治疗。通过在临床相关动物模型中进行有针对性的研究，主要研究者提出了一个新的假设，即心肌细胞衍生的黄嘌呤氧化酶介导线粒体的氧化损伤和容量超负荷时的左心室功能障碍。这些动物研究如果是积极的，可以为单独容量超负荷患者的黄嘌呤氧化酶抑制临床试验提供科学动力。