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.

项目概要 2 型糖尿病 (t2DM) 使患者容易患上使人衰弱的心血管疾病，包括急性心血管疾病缺血/再灌注（I/R）事件和慢性心肌梗塞（MI），两者都会促进心源性猝死死亡。 t2DM 的许多病理生理学并发症可能与高血糖介导的线粒体 ROS 过量产生，继发于线粒体分裂（裂变）。重要的是线粒体裂变是动力相关蛋白 1 (DRP1)，它是保守动力 GTP 酶的成员超家族。 DRP1 的过度表达促进了 DRP1 的功能重要性。线粒体膜电位去极化和细胞死亡，而其沉默或化学抑制减弱这些过程。改变 DRP1 和线粒体裂变对调节的影响 t2DM 中的心肌功能和心律失常仍不清楚，将在急性 I/R 的背景下进行检查损伤和慢性心肌梗死。 DRP1 的活性受多种激酶和磷酸酶（包括 AMP- 相关激酶 (AMPK) 是一种主要代谢传感器，在 2 型糖尿病的病理生理学中发挥着重要作用。通过控制 AMPK 还调节 ATP 生成和消耗过程之间的平衡 I/R 损伤和糖尿病心肌病的背景。本项目的总体前提基于以下几点证据线：1) DRP1 控制各种细胞类型（包括肌细胞）的线粒体分裂； 2）减少线粒体裂变可防止活性氧 (ROS) 诱导的线粒体去极化， mPTP开放和细胞凋亡； 3）高血糖介导需要DRP1相关的线粒体分裂各种细胞类型中 ROS 过量产生； 4) I/R 中急性 ROS 过量产生促进电功能障碍和心律失常，通过再生过程破坏线粒体膜电位线粒体 ROS 诱导的 ROS 释放； 5) 慢性 ROS 过量产生会导致不良的结构和机械改造； 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。该提案的核心内容是线粒体裂变及其 AMPK-DRP1 轴的调节在 2 型糖尿病相关心脏疾病中发挥核心作用功能障碍和心律失常。在目标 1 中，我们将确定 DRP1 介导的线粒体裂变的作用及其 AMPK 对糖尿病心脏对急性 ROS 相关再灌注心律失常的易感性的调节。在目标 2，我们将确定 AMPK-DRP1 轴损伤对 MI 后结构性损伤的影响程度糖尿病心脏的机电重塑和心律失常易感性。在目标 3 中，我们将测试靶向 DRP1 介导的线粒体分裂在逆转 MI 后心功能障碍中的治疗效果和糖尿病心脏的心律失常倾向。完成这些研究将产生新的机制见解研究线粒体分裂在 2 型糖尿病中的作用和调节，并发现新的线粒体靶向治疗方法应对这一重大公共卫生流行病的方法。