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: 8457056
• 负责人: Louis J. Dell'Italia
• 金额: $ 34.52万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457056
• 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.

描述（由申请人提供）：心脏中的体积超负荷（VO）促进了导致心力衰竭的生物能，结构和功能变化。然而，心肌代偿的机制以及导致VO导致的失败的进展尚不清楚。已经确定VO会增加黄嘌呤氧化酶（XO），活性氧和氮种（ROS/RNS）。在此提案中，我们将在VO引起的心脏衰竭的背景下整合两个关键的基础研究结果：1）XO作为VO引起的心脏中氧化损伤的根源； 2）VO VO介导的心脏衰竭病因中线粒体功能障碍的核心作用。该概念将通过追求有针对性的动物和人类研究的以下特定目的来测试。 AIM 1将检验以下假设：VO中增加XO活性会导致LV功能障碍通过大鼠慢性VO的心肌细胞线粒体功能障碍引起LV功能障碍。 AIM 2将检验以下假设：心肌细胞衍生的XO活性负责使用基因疗法使用基因疗法来敲除大鼠急性和慢性VO的XDH的心肌细胞MMP激活和线粒体功能障碍。 AIM 3将检验以下假设：XO抑制可减少心肌细胞氧化应激和线粒体功能障碍，并改善大鼠慢性ACF闭合后LV功能。这些实验将利用大鼠中的新基因治疗技术证明XO在心肌细胞中的原因和作用。心肌细胞功能的研究将使用动物细胞中的Seahorse XF24进行。提出的动物和心肌细胞研究将确定增加XO是否是纯VO的慢性延伸中氧化应激和线粒体功能障碍的关键调节剂。这些研究（如果阳性）可以为分离的VO患者的XO抑制作用提供科学动力。