Prolonged Diabetic Damage to Cardiac Mitochondria

糖尿病患者的并发症，如心肌病，会在多年的高血糖状态下发生。我们 他们提出，延长的时间进程源于对 线粒体DNA是由线粒体产生的活性氧物种(ROS)和 活性氮物种(RNS)。由于几个原因，线粒体dna特别容易受到损伤。 而且一些类型的损坏修复得很差。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。我们实验室研制了OVE26小鼠模型。 I型糖尿病，最适合慢性并发症的发展。心肌线粒体来源于 长期糖尿病OVE26小鼠表现出形态退化、谷胱甘肽含量降低和 增加了DNA损伤。线粒体抗氧化剂MnSOD活性增强的转基因小鼠， 靶向心脏，当进入OVE26背景时，表现出较少的收缩功能障碍，改善 线粒体形态和线粒体呼吸作用明显改善。我们建议 MnSOD过表达抑制线粒体基因组的损伤，这是改善的原因 心肌细胞功能。以检验ROS或RNS对线粒体DNA进行性损伤的假设 为促进糖尿病心肌病的发展，我们将实现以下具体目标： 目的1：评估线粒体DNA的突变和缺失，并将这些变化与 线粒体呼吸功能、电子传递链复合体活性、细胞和线粒体 ROS的产生和心肌细胞的收缩能力。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关系。关于OVE26糖尿病患者的背景 心肌过表达MnSOD和线粒体靶向保护线粒体DNA OGG1。我们还将确定DNA损伤和糖尿病心肌病是否都会因 将现有的OGG1基因敲除动物与我们的糖尿病小鼠杂交。目标3：评估系统治疗是否 使用结合自由过渡金属的试剂可以防止超氧化物形成更多的活性物种 破坏线粒体DNA。这些调查的结果可能直接适用于 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.