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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.

项目摘要/摘要 Fontan手术的长期幸存者中，超过50%的人患有单心室先天性心脏病心力衰竭，标准疗法(血管紧张素转换酶抑制剂、β受体阻滞剂)基本上无效。因此，一名少校治疗Fontan心/循环衰竭的挑战在于了解其独特的区别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。这个这项建议的首要目标是开发新的治疗靶点来保护心脏功能，并确定在Fontan循环患者的临床病程早期检测心脏/循环衰竭的生物标记物。我们先前已经确定慢性氧化应激诱导的线粒体损伤是方坦失败。我们假设氧化应激诱导心肌细胞释放受损的线粒体损害心脏(局部)和外周血管系统(血浆)的内皮功能方坦失败。我们通过细胞间通讯的镜头来研究这个一般性的问题心血管系统。在目标1中，我们将评估慢性非缺血性氧化应激在导致 Fontan衰竭时线粒体功能障碍。我们将使用心肌组织来评估脂质过氧化诱导线粒体功能障碍，与临床疾病的严重程度和损伤程度相关线粒体可以在胞外小泡中包装和运输，以调节细胞与细胞之间的通讯。在……里面目的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，这可能有助于作为一种新的治疗靶点。我们将评估心肌组织中内皮线粒体的动力学。 Fontan衰竭儿童通过细胞外评估心肌细胞和内皮细胞之间的通讯小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记物来监测患有和不患有Fontan衰竭的儿童的临床状况。请与控制进行比较。我们将展示携带氧化损伤的循环细胞外小泡线粒体导致外周血管内皮细胞功能障碍，决定细胞外小泡在启动代谢重新编程，无论是在局部还是在遥远的器官中。使用创新的方法，包括大量Fontan患者的3D人体组织成像和高通量定量蛋白质组学研究循环，我们将检验我们的假设，并检验新的线粒体靶向治疗的有效性，包括改变FDA批准的小分子拉米普肽的用途，以靶向脂质过氧化。通过更好的了解Fontan衰竭的独特机制，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。