Mitochondrial fission in diabetes-related arrhythmia

糖尿病相关心律失常中的线粒体分裂

• 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
• 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

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（t2 DM）使患者易患衰弱性心血管疾病，包括急性 缺血/再灌注（I/R）事件和慢性心肌梗死（MI），这两者都促进了突发性心脏病， 死亡2型糖尿病的许多病理生理并发症可能与高血糖介导的 线粒体ROS过度产生，继发于线粒体分裂（裂变）。重视 线粒体分裂是动力蛋白相关蛋白1（DRP 1），是保守的动力蛋白GT3的成员 超家族DRP 1的功能重要性通过其过度表达促进细胞凋亡这一事实得到强调。 线粒体膜电位去极化和细胞死亡，而其沉默或化学抑制 削弱这些进程。改变的DRP 1和线粒体分裂对调节 t2 DM的心肌功能和心律失常仍未知，将在急性I/R的背景下进行检查 损伤和慢性MI。DRP 1的活性受几种激酶和磷酸酶的调节，包括AMP- 相关激酶（AMPK），一种在2型糖尿病病理生理学中起中心作用的主要代谢传感器。通过控制 在ATP产生和消耗过程之间的平衡，AMPK还调节线粒体功能， I/R损伤和糖尿病心肌病的背景。本项目的总体前提基于以下几点 证据：1）DRP 1控制各种细胞类型（包括肌细胞）中的线粒体分裂; 2）减少 线粒体分裂防止活性氧（ROS）诱导的线粒体去极化， mPTP开放和细胞凋亡; 3）DRP 1相关的线粒体分裂是高血糖介导的细胞凋亡所必需的。 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 和心律失常通过破坏线粒体膜电位的再生过程， 线粒体ROS诱导的ROS释放; 5）慢性ROS过度产生促进不利的结构和 机械重塑;和6）在糖尿病中，AMPK激活通过改变DRP 1抑制线粒体分裂 在内皮细胞中特异性丝氨酸残基的磷酸化。这项建议的核心内容是， 线粒体分裂及其通过AMPK-DRP 1轴的调节在t2 DM相关的心脏疾病中起着中心作用。 功能障碍和心律失常。在目的1中，我们将确定DRP 1介导的线粒体分裂的作用及其对细胞增殖的影响。 AMPK调节糖尿病心脏对急性ROS相关再灌注心律失常的易感性。在 目的2，我们将确定AMPK-DRP 1轴损伤在多大程度上促进MI后结构性心肌梗死。 以及糖尿病心脏的电-机械重构和心律失常易感性。在目标3中，我们将测试 靶向DRP 1介导的线粒体分裂逆转MI后心功能不全的疗效 和心律失常倾向。这些研究的完成将产生新的机理见解 研究线粒体分裂在2型糖尿病中的作用和调节，并发现新的靶向治疗方法 应对这一重大公共卫生流行病的方法。