Prolonged Diabetic Damage to Cardiac Mitochondria

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，长期的时间进程源于损害的逐渐积累， 线粒体DNA由线粒体产生的活性氧（ROS）增加引起， 活性氮类（RNS）。由于几个原因，线粒体DNA特别容易受到损伤， 并且某些类型的损坏修复不良。我们假设线粒体DNA损伤是 糖尿病状态下的细胞和器官功能障碍。我们的实验室开发了OVE 26小鼠模型， I型糖尿病，最适合以下慢性并发症的发展。心肌线粒体 长期糖尿病OVE 26小鼠表现出形态学变性，谷胱甘肽含量降低， 增加DNA损伤。线粒体抗氧化剂MnSOD活性增加的转基因小鼠， 靶向心脏，当交叉到OVE 26背景上时，显示较少的收缩功能障碍，改善 线粒体形态和线粒体呼吸的显着改善。我们建议 MnSOD过表达抑制了线粒体基因组的损伤，这解释了改善的 心肌细胞功能为了验证ROS或RNS引起的进行性线粒体DNA损伤 有助于糖尿病心肌病的发展，我们将开展以下具体目标： 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，电子传递链复合物活性，细胞和线粒体 ROS生成和心肌细胞收缩性。目标2：确定是否存在因果关系 线粒体DNA损伤和糖尿病心肌病之间的联系关于OVE26糖尿病背景 线粒体DNA将受到MnSOD心脏过表达的保护， OGG1。我们还将确定是否DNA损伤和糖尿病心肌病都加剧了 将现有的OGG1敲除动物与我们的糖尿病小鼠进行交叉。目的3：评估全身治疗是否 与结合游离过渡金属的试剂一起使用可以防止超氧化物形成更具反应性的物质， 破坏线粒体DNA。这些调查的结果可能直接适用于发展 最大限度地减少或完全预防某些糖尿病并发症的新疗法。

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 morophological 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 transport chain complex activities, cellular and mitochondrial 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.