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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.

项目总结/摘要单心室先天性心脏病Fontan手术的长期存活者中，心力衰竭，标准治疗（ACE抑制剂，β-受体阻滞剂）在很大程度上无效。因此，一个主要的治疗Fontan心脏/循环衰竭的挑战在于了解其独特的机制，它从更常见的急性缺血性心力衰竭中寻找新的治疗靶点。的该提案的总体目标是开发新的治疗靶点，以保护心脏功能，并确定在Fontan循环患者的临床过程中早期检测心脏/循环衰竭的生物标志物。我们以前已经确定慢性氧化应激诱导的线粒体损伤是一个主要的机制，丰唐失败。我们假设氧化应激诱导心肌细胞释放受损的线粒体在心脏（局部）和外周血管系统（血浆）中损害内皮功能，丰唐失败。我们通过细胞间通讯的透镜来研究这个普遍的问题，心血管系统在目标1中，我们将评估慢性非缺血性氧化应激在引起脑缺血中的作用。 Fontan衰竭中的线粒体功能障碍。我们将使用心肌组织来评估脂质过氧化诱导的线粒体功能障碍，将线粒体功能障碍与临床疾病的严重程度以及如何损害线粒体可以在细胞外囊泡中包装和运输以介导细胞-细胞通讯。在目的2：探讨脂质过氧化损伤是否导致心肌线粒体损伤，功能我们将表明，心血管功能障碍是Fontan衰竭的一个重要组成部分，作为新的治疗靶点。我们将评估心肌组织中内皮线粒体动力学， Fontan衰竭的儿童，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。在目标3中，我们将确定循环生物标志物，以监测Fontan失败和非Fontan失败儿童的临床状态，对比一下控制。我们将证明，循环细胞外囊泡携带氧化损伤线粒体引起外周血管内皮功能障碍，决定了细胞外囊泡在启动局部和远端器官的代谢重编程。采用创新办法，包括 Fontan患者大型队列中的3D人体组织成像和高通量定量蛋白质组学循环，我们将测试我们的假设，并检查新的靶向治疗的有效性，包括将FDA批准的小分子依拉普利肽重新用于靶向脂质过氧化。通过更好了解Fontan失败的独特机制，我们的临床医生和线粒体专家团队和血管生物学准备开发新的策略来预防和治疗细胞能量衰竭和血管功能障碍。