Lipid Peroxidation-Induced Mitochondrial Injury Inhibits Vascular Function in Single Ventricle Congenital Heart Disease

脂质过氧化诱导的线粒体损伤抑制单心室先天性心脏病的血管功能

基本信息

批准号：
10735609
负责人：
Sushma Reddy
金额：
$ 66.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735609
关键词：
3-Dimensional 4 hydroxynonenal Acute Adrenergic beta-Antagonists Affect Angiotensin-Converting Enzyme Inhibitors Biogenesis Biological Markers Biology Blood Vessels Cardiac Cardiac Myocytes Cardiovascular system Cell Communication Cell Death Cell physiology Cells Child Chronic Circulation Clinical Coculture Techniques Common Ventricle Communication Complex Data Distant Endothelial Cells Endothelium FDA approved Failure Fibrosis Fontan Procedure Functional disorder Generations Goals Growth Factor Heart Heart failure Hypoxia Impairment Injury Ischemia Kidney Lipid Peroxidation Liver Long-Term Survivors Malondialdehyde Measures Mediating Membrane Metabolic Microvascular Dysfunction Mitochondria Mitochondrial Proteins Modification Monitor Myocardial Myocardial tissue Myocardium Operative Surgical Procedures Organ Oxidative Stress Oxidative Stress Induction Patients Peripheral Phenotype Phospholipids Plasma Play Population Prevention strategy Prevention therapy Proteomics Reporting Role Severities Severity of illness Single ventricle congenital heart disease Spatial Distribution Stress Techniques Testing Tissue imaging Tissues Treatment Failure Trees Vascular Diseases Vascular Endothelial Cell Ventricular Function angiogenesis biomarker identification circulating biomarkers cohort comparison control congenital heart disorder effectiveness evaluation extracellular vesicles functional status heart function heart preservation human tissue ineffective therapies inhibitor innovation ischemic cardiomyopathy lens mitochondrial dysfunction new therapeutic target novel therapeutics oxidation oxidative damage pressure prevent small molecule small molecule therapeutics targeted treatment therapeutic development vascular endothelial dysfunction

项目摘要

PROJECT SUMMARY/ABSTRACT Over 50% of long-term survivors of the Fontan operation with single ventricle congenital heart disease develop heart failure, for which standard therapies (ACE inhibitors, β-blockers) are largely ineffective. Thus, a major challenge in treating Fontan heart/circulation failure is in understanding its unique mechanisms that differentiate it from the more common acute ischemia-related heart failure and identifying new therapeutic targets. The overarching goal of this proposal is to develop new therapeutic targets to preserve heart function, and to identify biomarkers to detect heart/circulation failure earlier in the clinical course of patients with a Fontan circulation. We have previously identified chronic oxidative stress-induced mitochondrial injury as a major mechanism in Fontan failure. We hypothesize that oxidative stress induces cardiomyocytes to release damaged mitochondria that impair endothelial function in both the heart (local) and peripheral vasculature (plasma) in patients with Fontan failure. We examine this general question through the lens of cell-cell communication in the cardiovascular system. In Aim 1, we will evaluate the role of chronic non-ischemic oxidative stress in causing mitochondrial dysfunction in Fontan failure. We will use myocardial tissue to assess lipid peroxidation-induced mitochondrial dysfunction, correlate mitochondrial dysfunction with severity of clinical illness and how damaged mitochondria can be packaged and transported in extracellular vesicles to mediate cell-cell communication. In Aim 2, we will investigate whether lipid peroxidation-induced mitochondrial injury impairs cardiac vascular function. We will show that cardiac vascular dysfunction is a critical component of Fontan failure which may serve as a novel therapeutic target. We will assess endothelial mitochondrial dynamics in myocardial tissue from children with Fontan failure, assess cardiomyocyte and endothelial cell-cell communication via extracellular vesicles and phenotype the cardiac microvascular tree to assess for lipid peroxidation and cell death. In Aim 3, we will determine circulating biomarkers to monitor clinical status in children with and without Fontan failure and compare to control. We will show that circulating extracellular vesicles carrying oxidatively damaged mitochondria cause peripheral vascular endothelial dysfunction, determining the role of extracellular vesicles in initiating metabolic reprogramming, both locally and in distant organs. Using innovative approaches, including 3D human tissue imaging and high throughput quantitative proteomics, in a large cohort of patients with a Fontan circulation, we will test our hypothesis and examine the effectiveness of new mitochondrial-targeted therapies, including repurposing the FDA-approved small molecule elamipretide to target lipid peroxidation. Through better understanding of the unique mechanisms of Fontan failure, our team of clinicians and experts in mitochondrial and vascular biology are poised to develop new strategies for preventing and treating cellular energetic failure and vascular dysfunction.

项目摘要/摘要超过50％的Fontan操作的长期存活率具有单一通风先天性心脏病的发展心力衰竭，标准疗法（ACE抑制剂，β受体阻滞剂）在很大程度上无效。那，一个专业治疗方坦心脏/循环失败的挑战是了解其独特的机制它来自更常见的急性缺血相关心力衰竭并确定新的治疗靶标。这该建议的总体目标是开发新的治疗靶标，以保护心脏功能并确定生物标志物检测Fontan循环的患者临床病程早期的心脏/循环衰竭。我们先前已经确定了慢性氧化应激诱导的线粒体损伤是一种主要机制丰丹失败。我们假设氧化应激会诱导心肌细胞释放受损的线粒体这种损害了心脏（局部）和周围脉管系统（等离子体）的内皮功能丰丹失败。我们通过细胞电池通信的镜头检查了这个一般问题心血管系统。在AIM 1中，我们将评估慢性非缺血性氧化应激在引起的作用方丹失效的线粒体功能障碍。我们将使用心肌组织评估脂质过氧化诱导的线粒体功能障碍，线粒体功能障碍与临床疾病的严重程度以及如何受损线粒体可以包装并在细胞外蔬菜中运输，以介导细胞 - 细胞通信。在 AIM 2，我们将研究脂质过氧化诱导的线粒体损伤是否损害心脏血管功能。我们将证明心脏血管功能障碍是Fontan衰竭的关键组成部分，可以使用作为一种新型的治疗靶标。我们将评估心肌组织中的内皮线粒体动力学 Fontan衰竭，评估心肌细胞和内皮细胞 - 细胞通信的儿童通过细胞外囊泡和表型心脏微血管树，以评估脂质过氧化和细胞死亡。在AIM 3中，我们将确定循环生物标志物以监测有或没有Fontan失败儿童的临床状况以及比较控制。我们将证明携带氧化损坏的细胞外蔬菜线粒体引起周围血管内皮功能障碍，确定细胞外蔬菜在在本地和遥远的器官中启动代谢重编程。使用创新的方法，包括 3D人体组织成像和高吞吐量定量蛋白质组学，大量具有丰富的患者循环，我们将检验我们的假设并检查新线粒体靶向疗法的有效性，包括重新利用FDA批准的小分子elamipretide以靶向脂质过氧化。通过更好了解方丹失败的独特机制，我们的临床医生团队和线粒体专家和血管生物学被毒化以制定预防和治疗细胞能量衰竭的新策略和血管功能障碍。