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Prolonged Diabetic Damage to Cardiac Mitochondria

长期糖尿病对心脏线粒体的损害

基本信息

批准号：
7334221
负责人：
PAUL N EPSTEIN
金额：
$ 34.13万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
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/7334221
关键词：
8-Oxoguanine DNA Glycosylase Accounting Age Animal Model Animals Antioxidants Binding Cardiac Cardiac Myocytes Cardiomyopathies Cell Nucleus Chronic Complex Complications of Diabetes Mellitus DNA Damage DNA Repair DNA Repair Enzymes Data Deletion Mutation Development Diabetes Mellitus Diabetic mouse Elderly Electron Transport Enzymes Exhibits Functional disorder Generations Glutathione Heart Histones Human Hydroxyl Radical Hyperglycemia Individual Insulin-Dependent Diabetes Mellitus Investigation Laboratories Life Lyase Mitochondria Mitochondrial DNA Morphology Mus OGG1 gene Organ Pathology Patients Peroxonitrite Personal Satisfaction Process Production Protein Overexpression Proteins Publishing Rate Reactive Nitrogen Species Reactive Oxygen Species Research Personnel Respiration Respiratory physiology Sampling Source Superoxides Systemic Therapy Testing Time Transgenic Mice Transition Elements Week Work cell type diabetic diabetic cardiomyopathy improved knockout animal mitochondrial genome mouse model prevent programs repaired stem

项目摘要

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.

糖尿病患者的并发症如心肌病在多年的高血糖中发展。我们