Molecular Basis of Postischemic Maladaptation in the Insulin Resistant Heart

胰岛素抵抗心脏缺血后适应不良的分子基础

• 批准号: 9899301
• 负责人: Romain Harmancey
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899301
• 关键词: Acute myocardial infarction; Address; Alleles; Anions; Antioxidants; Bioenergetics; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Carrier Proteins; Cause of Death; Cell Respiration; Ceramides; Cessation of life; Coronary; Coronary heart disease; Data; Defect; Diet; Epidemic; Fatty Acids; Functional disorder; Gene Delivery; Generations; Goals; Grant; Heart; Heart Diseases; Impairment; Individual; Insulin Resistance; Intervention; Ischemia; Knowledge; Link; Medium chain fatty acid; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Mutation; Myocardial; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Oxides; Patients; Pharmacology; Production; Property; Rattus; Recovery; Recovery of Function; Reperfusion Therapy; Structure; Testing; Therapeutic; Time; Type 2 diabetic; United States; Ventricular Remodeling; Work; base; diabetic patient; fatty acid metabolism; fatty acid oxidation; fatty acid supplementation; heart function; high risk; improved; in vivo Model; insulin signaling; long chain fatty acid; mitochondrial dysfunction; mitochondrial uncoupling protein 3; mortality; novel; outcome forecast; oxidation

ABSTRACT Type 2 diabetes has reached epidemic proportions and is a leading cause of coronary heart disease in the United States. Insulin resistance, a hallmark of type 2 diabetes, is associated with a 2 to 4 times higher risk of cardiac morbidity and mortality following acute myocardial infarction (MI). The goals of this project are to elucidate the molecular mechanisms linking insulin resistance to poor cardiac recovery after MI and to apply this knowledge to develop therapeutic strategies for improving recovery of cardiac function in diabetic patients at reperfusion. Uncoupling protein 3 (UCP3) is a mitochondrial anion carrier protein with antioxidant properties involved in the metabolism of long-chain fatty acids (LCFA). Muscle UCP3 content is 50% lower in type 2 diabetic patients compared with healthy control subjects. A similar decrease is observed in the heart of mice and rats with insulin resistance and type 2 diabetes. Using CRISPR/Cas9-targeted mutation in rats, we have gathered preliminary data showing that a 50% decrease in cardiac UCP3 levels is sufficient to significantly impair contractile recovery following ischemia. Our results further suggest that decreased functional recovery of insulin resistant and UCP3 deficient hearts after ischemia is caused by a limited capacity to oxidize LCFA at reperfusion, a defect that can be rescued by supplying medium-chain fatty acids (MCFA) as an alternative fuel. Besides the bioenergetic deficit, impaired LCFA oxidation is known to cause a toxic accumulation of long-chain ceramides and to increase oxidative stress. Therefore, we hypothesize that decreased UCP3 impairs the recovery of systolic function in insulin resistant hearts following MI by limiting myocardial LCFA oxidation, increasing mitochondrial dysfunction, and increasing cardiac myocyte death at reperfusion. Three aims will address this hypothesis in mouse and rat models of dietary, pharmacologically, or genetically induced myocardial insulin resistance or UCP3 deficiency (40-50% decrease) in a multisystem approach combining in vivo models of MI/reperfusion to isolated beating hearts to isolated mitochondria. Aim 1 will examine the effect of UCP3 deficiency and of its reversal on cardiac structural and functional recovery post MI/reperfusion. Aim 2 will investigate the molecular consequences of UCP3 deficiency for mitochondrial function and cardiac oxidative metabolism during ischemia/reperfusion. Aim 3 will test whether a metabolic intervention based on increasing supply of MCFA to the heart can reverse these abnormalities. We expect this project to reveal a novel molecular mechanism responsible for the poor prognosis of type 2 diabetic patients following MI/reperfusion, and that it will provide the basis for additional studies to test MCFA-based treatments as a metabolic strategy to improve cardiac outcomes in T2DM patients undergoing reperfusion after MI.

抽象的 2型糖尿病已达到流行比例，是冠心病的主要原因 美国。胰岛素抵抗是2型糖尿病的标志，与增加的风险高2至4倍 急性心肌梗塞（MI）后心脏发病率和死亡率。该项目的目标是 阐明将胰岛素抵抗与MI后心脏恢复不良的分子机制，并应用 这种知识以开发用于改善糖尿病患者心脏功能恢复的治疗策略 在再灌注中。解偶联蛋白3（UCP3）是具有抗氧化特性的线粒体阴离子载体蛋白 参与长链脂肪酸（LCFA）的代谢。肌肉UCP3含量在2型中低50％ 与健康对照组相比，糖尿病患者。在小鼠的心脏中观察到类似的下降 和具有胰岛素抵抗和2型糖尿病的大鼠。在大鼠中使用CRISPR/CAS9靶向突变，我们有 收集的初步数据表明，心脏UCP3水平下降50％足以显着 缺血后的收缩回收率受损。我们的结果进一步表明功能恢复降低 缺血后，胰岛素抵抗和UCP3不足的心脏是由氧化LCFA的能力有限引起的 再灌注，可以通过提供中链脂肪酸（MCFA）作为替代燃料来挽救的缺陷。 除了生物能赤字外，LCFA氧化受损还会引起长链有毒的积累 神经酰胺并增加氧化应激。因此，我们假设降低的UCP3损害了 通过限制心肌LCFA，在MI之后恢复胰岛素耐药心脏的收缩功能 氧化，线粒体功能障碍的增加，并在再灌注时增加心肌细胞死亡。 三个目标将在饮食，药理或遗传学的小鼠和大鼠模型中解决这一假设。 多系统方法中诱导心肌胰岛素抵抗或UCP3缺乏症（降低40-50％） 将MI/再灌注的体内模型结合到孤立的线粒体中。目标1意志 检查UCP3缺乏及其逆转对心脏结构和功能恢复后的影响 MI/再灌注。 AIM 2将研究线粒体UCP3缺乏的分子后果 缺血/再灌注期间的功能和心脏氧化代谢。 AIM 3将测试是否代谢 基于MCFA供应增加心脏的干预可以扭转这些异常。我们期望这一点 项目揭示了导致2型糖尿病患者预后不良的新型分子机制 在MI/再灌注之后，它将为测试基于MCFA治疗的其他研究提供基础 作为改善MI后再灌注的T2DM患者心脏结局的代谢策略。