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程度，是冠心病的主要原因 美国。胰岛素抵抗是 2 型糖尿病的一个标志，与 2 至 4 倍的高风险相关 急性心肌梗死（MI）后的心脏发病率和死亡率。该项目的目标是 阐明胰岛素抵抗与 MI 后心脏恢复不良之间的分子机制，并应用 这些知识可用于制定改善糖尿病患者心功能恢复的治疗策略 再灌注时。解偶联蛋白 3 (UCP3) 是一种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。 2型肌肉UCP3含量降低50% 糖尿病患者与健康对照者进行比较。在小鼠心脏中也观察到类似的减少 以及患有胰岛素抵抗和 2 型糖尿病的大鼠。在大鼠中使用 CRISPR/Cas9 靶向突变，我们得到了 收集的初步数据显示，心脏 UCP3 水平降低 50% 足以显着 损害缺血后的收缩恢复。我们的结果进一步表明功能恢复下降 缺血后胰岛素抵抗和 UCP3 缺乏的心脏是由 LCFA 氧化能力有限引起的 再灌注，这种缺陷可以通过提供中链脂肪酸（MCFA）作为替代燃料来弥补。 除了生物能不足之外，已知 LCFA 氧化受损还会导致长链有毒物质的积累。 神经酰胺并增加氧化应激。因此，我们假设 UCP3 的减少会损害 通过限制心肌 LCFA 恢复 MI 后胰岛素抵抗心脏的收缩功能 氧化，增加线粒体功能障碍，并增加再灌注时心肌细胞死亡。 三个目标将在饮食、药理学或遗传的小鼠和大鼠模型中解决这一假设 通过多系统方法诱导心肌胰岛素抵抗或 UCP3 缺乏（减少 40-50%） 将 MI/再灌注体内模型与离体跳动心脏和离体线粒体相结合。目标1将 检查 UCP3 缺乏及其逆转对术后心脏结构和功能恢复的影响 心肌梗塞/再灌注。目标 2 将研究 UCP3 缺乏对线粒体的分子后果 缺血/再灌注期间的功能和心脏氧化代谢。目标 3 将测试代谢是否 基于增加心脏 MCFA 供应的干预可以逆转这些异常。我们期待这个 该项目旨在揭示导致 2 型糖尿病患者预后不良的新分子机制 MI/再灌注后，它将为测试基于 MCFA 的治疗的其他研究提供基础 作为改善 MI 后再灌注 T2DM 患者心脏结局的代谢策略。