Improving mitochondrial function to protect against myocardial ischemia/reperfusion

改善线粒体功能以防止心肌缺血/再灌注

• 批准号: 9218501
• 负责人: QINGLIN YANG
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218501
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Adenoviruses; Affect; Attenuated; Biochemical; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiomyopathies; Cardiovascular system; Chickens; Clinical; Congestive Heart Failure; Coupling; Defect; Dependovirus; Disease; Down Syndrome; Energy Metabolism; Enhancers; Enzymes; Escherichia coli; Gene Targeting; Generations; Genes; Heart; Impairment; In Vitro; Ischemia; Knock-out; Knockout Mice; Lead; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Mitochondrial Proton-Translocating ATPases; Molecular; Morphology; Multienzyme Complexes; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Names; Organ; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; PPAR alpha; Patients; Performance; Peroxisome Proliferator-Activated Receptors; Pilot Projects; Play; Production; Proteins; Protons; Regulation; Reperfusion Injury; Reperfusion Therapy; Reservations; Respiration; Role; Satellite Viruses; Serotyping; Signal Transduction; Skeletal Muscle; Structure; Tamoxifen; Testing; Therapeutic; Tissues; Transgenic Organisms; Troponin T; Viral Vector; Work; base; gain of function; gene therapy; genetic manipulation; heart metabolism; human disease; improved; in vivo; innovation; insight; ischemic cardiomyopathy; mitochondrial membrane; mitochondrial metabolism; mouse model; new therapeutic target; novel; overexpression; pre-clinical; prevent; promoter; success; therapeutic gene

Myocardial ischemia/reperfusion (IR) injury is the main clinical challenge of adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. It is well established that myocardial ATP depletion is a key feature of myocardial ischemia and heart failure1. Improving myocardial energy metabolism has been a well- known target to protect the heart from IR injury, but with little success. " ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure. However, our understanding of the regulation of energy metabolism and mitochondrial function in the energy demanding heart remains poor. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1 with unknown function. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits α and β of ATP synthase F1 sector. We were excited to find that ES1 works as an enhancer of ATP production by increasing ATP synthesis and inhibiting ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart subjected to myocardial IR. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in hearts with myocardial IR injury of patients and mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from myocardial IR via its role in facilitating cardiac energy production/reservation. To test this central hypothesis, we will first define the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We will then determine if transgenic and adenoviral-associated virus-mediated ES1 overexpression in the heart protects the heart against myocardial IR injury by its role in regulating energy metabolism. These studies will provide novel insights into how to manipulate energy metabolism to protect the heart from myocardial IR injury. Furthermore, these new fundamental scientific findings will have broader implications in diseases related to other organs and tissues.

心肌缺血/再灌注（IR）损伤是心肌缺血/再灌注损伤的主要临床挑战。 心肌缺血、心脏手术或循环停止后的心血管结局。 众所周知，心肌ATP耗竭是心肌缺血的一个关键特征。 缺血和心力衰竭1.改善心肌能量代谢一直是一个很好的- 已知的目标，以保护心脏免受IR损伤，但收效甚微。" ATP合成酶是线粒体中产生ATP的关键酶复合体， 在线粒体功能中的核心作用。ATP合酶的功能缺陷可导致 加重人类疾病，如心肌病和充血性心力衰竭。 然而，我们对能量代谢和线粒体调节的理解， 需要能量的心脏的功能仍然很差。我们最近发现了一个 PPAR-target基因编码一种功能未知的线粒体蛋白ES 1。 初步研究表明，ES 1是一种线粒体蛋白， ATP合成酶F1区的α和β亚基。我们很高兴地发现，ES 1的工作原理是 通过增加ATP合成和抑制ATP生成的增强剂 水解然而，目前尚不清楚ES 1是否同样调节ATP的产生。 有趣的是，我们的初步研究表明，ES 1 心肌缺血再灌注损伤的患者和小鼠心脏中蛋白水平降低。 在条件转基因小鼠和基因打靶小鼠的初步研究基础上， 假设ES 1是一种新治疗靶点， 心肌IR通过其促进心脏能量产生/储备的作用。到 为了检验这个中心假设，我们将首先将ES 1的作用定义为内生的 ATP合酶的调节剂，并作为线粒体结构/功能的决定因素， 心然后我们将确定转基因和腺病毒相关病毒介导的 心脏中ES 1的过表达通过其对心肌IR损伤的保护作用， 调节能量代谢的作用。这些研究将提供新的见解， 控制能量代谢，保护心脏免受心肌IR损伤。 此外，这些新的基础科学发现将对以下方面产生更广泛的影响： 与其他器官和组织有关的疾病。