Mitochondrial fission in diabetes-related arrhythmia

糖尿病相关心律失常中的线粒体分裂

基本信息

批准号：
10418766
负责人：
FADI GABRIEL AKAR
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418766
关键词：
Action Potentials Acute Apoptosis Area Arrhythmia Attenuated Bioenergetics Blood Glucose Cardiovascular Diseases Cell Death Chemicals Chronic Consumption Development Diabetes Mellitus Diet Dominant-Negative Mutation Dynamin Dynamin I Electrophysiology (science)Endothelial Cells Epidemic Equilibrium Event Fatty acid glycerol esters Female Fibrosis Functional disorder Glycosylated hemoglobin A Guanosine Triphosphate Phosphohydrolases Heart Hyperglycemia Hypertrophy Impairment Injury Insulin Resistance Ischemia Link Measurement Mechanics Mediating Membrane Potentials Metabolic Mitochondria Modeling Molecular Monitor Morphology Mus Muscle Cells Myocardial Myocardial Infarction Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Obesity Optics Organ Oxidative Stress Oxygen Consumption Pathologic Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Predisposition Process Protein Dynamics Proteins Public Health Randomized Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Resistance Risk Role Secondary to Serine Site Sucrose Testing Time Tissues Treatment Efficacy Up-Regulation base cell type comparative efficacy constriction delivery vehicle density diabetic diabetic cardiomyopathy endothelial dysfunction glucose tolerance hemodynamics imaging study in vivo insight knock-down male member metabolic imaging mitochondrial membrane mutant myocardial infarct sizing novel overexpression prospective protein expression regenerative response sensor sham surgery small molecule sudden cardiac death targeted treatment therapeutic evaluation vector control

项目摘要

PROJECT SUMMARY Type 2 diabetes mellitus (t2DM) predisposes patients to debilitating cardiovascular disorders, including acute ischemia/reperfusion (I/R) events and chronic myocardial infarction (MI), both of which promote sudden cardiac death. Many of the pathophysiological complications of t2DM can be linked to hyperglycemia-mediated mitochondrial ROS overproduction that is secondary to mitochondrial division (fission). Of importance to mitochondrial fission is the dynamin related protein 1 (DRP1), a member of the conserved dynamin GTPase superfamily. The functional importance of DRP1 is underscored by the fact that its over-expression promotes mitochondrial membrane potential depolarization and cell death whereas its silencing or chemical inhibition attenuates these processes. The implications of altered DRP1 and mitochondrial fission for modulating myocardial function and arrhythmias in t2DM remain unknown and will be examined in the context of acute I/R injury and chronic MI. The activity of DRP1 is regulated by several kinases and phosphatases including the AMP- related kinase (AMPK), a master metabolic sensor that is central in the pathophysiology of t2DM. By controlling the balance between ATP generating and consuming processes, AMPK also regulates mitochondrial function in the settings of I/R Injury and diabetic cardiomyopathy. The overall premise of this project is based on the following lines of evidence: 1) DRP1 controls mitochondrial division in various cell types, including myocytes; 2) Decreased mitochondrial fission protects against reactive oxygen species (ROS)-induced mitochondrial depolarization, mPTP opening, and apoptosis; 3) DRP1-related mitochondrial fission is required for hyperglycemia-mediated ROS overproduction in various cell types; 4) Acute ROS overproduction in I/R promotes electrical dysfunction and arrhythmia by destabilizing the mitochondrial membrane potential through the regenerative process of mitochondrial ROS-induced ROS-release; 5) Chronic ROS overproduction promotes adverse structural and mechanical remodeling; and 6) In diabetes, AMPK activation inhibits mitochondrial fission by altering DRP1 phosphorylation at specific serine residues in endothelial cells. The central tenant of this proposal is that mitochondrial fission and its regulation by an AMPK-DRP1 axis plays a central role in t2DM-related cardiac dysfunction and arrhythmia. In Aim 1, we will determine the role of DRP1-mediated mitochondrial fission and its regulation by AMPK in the susceptibility of the diabetic heart to acute ROS-related reperfusion arrhythmias. In Aim 2, we will determine the extent to which impairment in the AMPK-DRP1 axis contributes to post-MI structural and electro-mechanical remodeling and arrhythmia susceptibility in the diabetic heart. In Aim 3, we will test the therapeutic efficacy of targeting DRP1-mediated mitochondrial fission in reversing post-MI cardiac dysfunction and arrhythmia propensity in the diabetic heart. Completion of these studies will yield new mechanistic insights into the role and regulation of mitochondrial fission in t2DM, and uncover novel mitochondria-targeted therapeutic approaches for this major public health epidemic.

项目摘要 2型糖尿病（T2DM）易患患者的心血管疾病，包括急性缺血/再灌注（I/R）事件和慢性心肌梗塞（MI），这两者都促进心脏突然心脏死亡。 T2DM的许多病理生理并发症可以与高血糖介导的线粒体的线粒体ROS过量生产继发于线粒体分裂（裂变）。重要性线粒体裂变是Dynamin相关蛋白1（DRP1），这是保守动力蛋白GTPase的成员超家族。 DRP1的功能重要性是由于其过表达促进的事实强调了线粒体膜电势去极化和细胞死亡，而其沉默或化学抑制作用减弱这些过程。 DRP1和线粒体裂变改变的含义 T2DM中的心肌功能和心律不齐仍然未知，将在急性I/R的背景下检查受伤和慢性MI。 DRP1的活性受几种激酶和磷酸酶（包括AMP-）的调节相关激酶（AMPK），一种主要的代谢传感器，在T2DM的病理生理中是中心的。通过控制 ATP生成和消费过程之间的平衡，AMPK还调节线粒体功能 I/R损伤和糖尿病心肌病的设置。该项目的总体前提是基于以下证据线：1）DRP1控制各种细胞类型的线粒体分裂，包括肌细胞； 2）减少线粒体裂变可预防活性氧（ROS）诱导的线粒体去极化， MPTP开放和凋亡； 3）高血糖介导的与DRP1相关的线粒体裂变需要 ROS在各种细胞类型中产生过量； 4）I/R中的急性ROS过量产生促进电气功能障碍通过通过再生过程破坏线粒体膜电位，通过破坏心律不齐线粒体ROS诱导的ROS释放； 5）慢性ROS生产促进不良结构和机械重塑； 6）在糖尿病中，AMPK激活通过改变DRP1抑制线粒体裂变内皮细胞中特定丝氨酸残基的磷酸化。该提议的中心租户是线粒体裂变及其通过AMPK-DRP1轴调节在T2DM相关心脏中起着核心作用功能障碍和心律不齐。在AIM 1中，我们将确定DRP1介导的线粒体裂变及其的作用 AMPK调节糖尿病心脏对急性ROS相关的再灌注心律失常的敏感性。在 AIM 2，我们将确定AMPK-DRP1轴的损伤在多大程度上有助于MI后结构以及糖尿病心脏中的电力重塑和心律不齐的敏感性。在AIM 3中，我们将测试靶向DRP1介导的线粒体裂变的治疗功效在逆转MI心脏功能障碍中糖尿病心脏中的心律不齐倾向。这些研究的完成将产生新的机械见解进入T2DM中线粒体裂变的作用和调节，并发现新的线粒体靶向治疗这种主要公共卫生流行的方法。