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.

项目概要/摘要超过 50% 的 Fontan 手术长期幸存者患有单心室先天性心脏病心力衰竭，标准疗法（ACE抑制剂、β受体阻滞剂）基本上无效，因此，这是一个主要的问题。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相关心力衰竭中分离出来，并确定新的治疗靶点。该提案的总体目标是开发新的治疗靶点以保护心脏功能，并确定生物标志物可在 Fontan 循环患者的临床过程中早期检测心脏/循环衰竭。我们之前已经发现慢性氧化应激诱导的线粒体损伤是线粒体损伤的主要机制。我们勇敢地面对氧化应激会诱导心肌细胞释放受损的线粒体。损害患者心脏（局部）和外周血管（血浆）的内皮功能我们通过细胞间通讯的视角来研究这个普遍问题。在目标 1 中，我们将评估慢性非缺血性氧化应激在引起心血管系统疾病中的作用。 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引起的。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受损程度相关联线粒体可以在细胞外囊泡中包装和运输以介导细胞间通讯。目标2，我们将研究脂质过氧化诱导的线粒体损伤是否损害心血管我们将证明心血管功能障碍是 Fontan 衰竭的一个关键组成部分，这可能有助于改善功能。作为一种新的治疗靶点，我们将评估心肌组织中的内皮线粒体动力学。患有 Fontan 衰竭的儿童，通过细胞外评估心肌细胞和内皮细胞间的通讯对心脏微血管树进行囊泡和表型分析，以评估脂质过氧化和细胞死亡。我们将确定循环生物标志物来监测患有和不患有 Fontan 衰竭的儿童的临床状态，以及我们将显示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，决定细胞外囊泡在使用创新方法，包括在局部和远处器官启动代谢重编程。在一大群患有 Fontan 的患者中进行 3D 人体组织成像和高通量定量蛋白质组学循环中，我们将测试我们的假设并检查新的线粒体靶向疗法的有效性，包括重新利用 FDA 批准的小分子埃拉米普肽，以更好地靶向脂质过氧化。了解 Fontan 失败的独特机制，我们的线粒体上级和专家团队血管生物学准备开发预防和治疗细胞能量衰竭的新策略和血管功能障碍。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects.

线粒体靶向治疗可预防孕产妇糖尿病引起的先天性心脏缺陷。

DOI：
发表时间：
2024-03
期刊：
影响因子：
0
作者：
Reddy; Sushma
通讯作者：
Sushma

Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Congenital Heart Disease.

钠-葡萄糖协同转运蛋白 2 抑制剂对先天性心脏病成人患者的影响。

DOI：
发表时间：
2024-04-16
期刊：
影响因子：
24
作者：
Neijenhuis, Ralph M L;MacDonald, Simon T;Zemrak, Filip;Mertens, Bart J A;Dinsdale, Anna;Hunter, Amanda;Walker, Niki L;Swan, Lorna;Reddy, Sushma;Rotmans, Joris I;Jukema, J Wouter;Jongbloed, Monique R M;Veldtman, Gruschen R;Egorova, Anastasia D
通讯作者：
Egorova, Anastasia D