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.

项目总结 2型糖尿病(T2 DM)使患者容易患上衰弱的心血管疾病，包括急性 缺血/再灌注(I/R)事件和慢性心肌梗死(MI)，两者都促进心脏骤停 死亡。T2 DM的许多病理生理并发症都与高血糖有关 线粒体ROS过量生产，是线粒体分裂(分裂)的次要原因。对…很重要 线粒体分裂是动力蛋白相关蛋白1(Drp1)，是保守的动力蛋白GTP酶成员 超级大家庭。DRp1的功能重要性被其过度表达促进 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。改变的DRp1和线粒体分裂对调控的意义 T2 DM患者的心肌功能和心律失常仍不清楚，将在急性I/R的情况下进行检查 损伤和慢性心肌梗死。Drp1的活性受多种激酶和磷酸酶的调节，其中包括AMP-1。 相关激酶(AMPK)，一种主要的代谢感受器，在T2 DM的病理生理学中起中心作用。通过控制 在ATP产生和消耗过程之间的平衡，AMPK也调节线粒体的功能 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几个方面 证据：1)drp1控制各种细胞类型的线粒体分裂，包括心肌细胞；2)减少 线粒体分裂可对抗活性氧(ROS)诱导的线粒体去极化， MPTP开放与细胞凋亡；3)高血糖需要Drp1相关的线粒体分裂 不同细胞类型的ROS过度产生；4)I/R中急性ROS过度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过度生产促进不利的结构和 6)在糖尿病中，AMPK的激活通过改变Drp1抑制线粒体的分裂 内皮细胞中特定丝氨酸残基的磷酸化。这项提案的主要租户是 线粒体分裂及其AMPK-DRp1轴的调节在T2 DM相关心脏中起核心作用 功能障碍和心律失常。在目标1中，我们将确定Drp1介导的线粒体分裂的作用及其 AMPK对糖尿病心脏对急性ROS相关再灌注性心律失常易感性的调节。在……里面 目的2，我们将确定AMPK-Drp1轴的损伤对心肌梗死后结构性损伤的影响程度 糖尿病心脏的机电重构和心律失常易感性。在目标3中，我们将测试 靶向Drp1介导的线粒体裂变逆转心肌梗死后心功能不全的疗效 糖尿病心脏的心律失常倾向。这些研究的完成将产生新的机械论见解 探讨线粒体分裂在T2 DM中的作用和调控，探索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。