Prolonged Diabetic Damage to Cardiac Mitochondria

长期糖尿病对心脏线粒体的损​​害

• 批准号: 7027938
• 负责人: PAUL N EPSTEIN
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027938
• 关键词: DNA damage; cardiac myocytes; cardiovascular disorder prevention; cell morphology; chemical binding; chemoprevention; chronic disease /disorder; diabetic cardiomyopathy; electron transport; free radical oxygen; gene deletion mutation; gene expression; gene mutation; genetically modified animals; heart contraction; heart disorder chemotherapy; laboratory mouse; metal oxide; mitochondrial DNA; mitochondrial disease /disorder; muscle contraction; nitrogen oxides; nonhuman therapy evaluation; oxidative stress; respiratory function; superoxides

DESCRIPTION (provided by applicant): In diabetic patients complications such as cardiomyopathy develop over many years of hyperglycemia. We are proposing that the prolonged time course stems from the gradual accumulation of damage to mitochondrial DNA caused by increased mitochondrial generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). For several reasons, mitochondrial DNA is especially vulnerable to damage and some types of damage are poorly repaired. We hypothesize that mitochondrial DNA damage is causal for cellular and organ dysfunction in the diabetic state. Our laboratory developed the OVE26 mouse model of Type I diabetes, optimal for following chronic development of complications. Cardiac mitochondria from long-term diabetic OVE26 mice exhibit morphological degeneration, decreased glutathione content and increased DNA damage. Transgenic mice with increased activity of the mitochondrial antioxidant MnSOD, targeted to the heart, when crossed onto the OVE26 background, show less contractile dysfunction, improved mitochondrial morphology and a significant improvement in mitochondrial respiration. We propose that MnSOD overexpression suppresses damage to the mitochondrial genome and that this accounts for improved cardiomyocyte function. To test the hypothesis that progressive mitochondrial DNA damage by ROS or RNS contributes to the development of diabetic cardiomyopathy we will carry out the following Specific Aims: Aim 1: Evaluate mutations and deletions in mitochondrial DNA and correlate these changes with mitochondrial respiratory function, electron ROS generation and cardiomyocyte contractility. Aim 2: Determine if there is a cause and effect relationship between mitochondrial DNA damage and diabetic cardiomyopathy. On the OVE26 diabetic background mitochondrial DNA will be protected by cardiac overexpression of MnSOD and mitochondrial targeted OGG1. We will also determine whether both DNA damage and diabetic cardiomyopathy are exacerbated by crossing existing OGG1 knockout animals to our diabetic mice. Aim 3: Assess whether systemic therapy with agents that bind free transition metals can prevent superoxide from forming more reactive species that damage mitochondrial DNA. Results of these investigations may be directly applicable to the development of new therapies which minimize or absolutely prevent certain diabetic complications.

描述（由申请人提供）： 在糖尿病患者中，并发症如心肌病在多年的高血糖中发展。我们提出，延长的时间过程源于线粒体DNA损伤的逐渐积累，线粒体产生的活性氧（ROS）和活性氮（RNS）的增加。由于几个原因，线粒体DNA特别容易受到损伤，并且某些类型的损伤修复不良。我们假设线粒体DNA损伤是糖尿病状态下细胞和器官功能障碍的原因。我们的实验室开发了I型糖尿病的OVE 26小鼠模型，最适合于以下并发症的慢性发展。来自长期糖尿病OVE 26小鼠的心脏线粒体表现出形态学变性、谷胱甘肽含量降低和DNA损伤增加。当与OVE 26背景杂交时，具有针对心脏的线粒体抗氧化剂MnSOD活性增加的转基因小鼠显示出较少的收缩功能障碍，改善的线粒体形态和线粒体呼吸的显著改善。我们认为MnSOD过表达抑制了线粒体基因组的损伤，这是改善心肌细胞功能的原因。为了验证ROS或RNS导致的线粒体DNA进行性损伤有助于糖尿病心肌病发展的假设，我们将进行以下具体目的：目的1：评估线粒体DNA中的突变和缺失，并将这些变化与线粒体呼吸功能、电子ROS产生和心肌细胞收缩性相关联。目的2：确定线粒体DNA损伤与糖尿病心肌病之间是否存在因果关系。在OVE 26糖尿病背景下，MnSOD和线粒体靶向OGG1的心脏过表达将保护线粒体DNA。我们还将确定通过将现有的OGG1敲除动物与我们的糖尿病小鼠杂交是否会加剧DNA损伤和糖尿病心肌病。目标三：评估使用结合游离过渡金属的药物进行全身治疗是否可以防止超氧化物形成更具反应性的物质，从而损伤线粒体DNA。这些研究的结果可能直接适用于开发新的治疗方法，最大限度地减少或完全预防某些糖尿病并发症。