Extracellular redox biology links to metabolic and mitochondrial dysfunction in pulmonary hypertension

细胞外氧化还原生物学与肺动脉高压的代谢和线粒体功能障碍有关

基本信息

批准号：
10750457
负责人：
Daniel Antonio Colon Hidalgo
金额：
$ 6.94万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2023-09-02 至 2024-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10750457
关键词：
Adenosine Monophosphate Affinity Amino Acid Substitution Animal Model Attenuated Automobile Driving Binding Bioenergetics Biogenesis Biology Blood Vessels Cardiac Catheterization Procedures Cell Hypoxia Cell Proliferation Cessation of life Chronic Data Development Electron Spin Resonance Spectroscopy Electron Transport Endothelial Cells Endothelium Event Exposure to Family Fatty Acids Future Genes Genus Hippocampus Goals Histologic Homeostasis Human Hypoxia KDR gene Knowledge Link Lung Measurement Measures Metabolic Metabolic dysfunction Metabolism Microscopy Mitochondria Modeling Mouse Strains Mus Outcome Outcome Measure Oxidation-Reduction Oxidative Phosphorylation Pathogenesis Patients Phenotype Physiologic intraventricular pressure Plasma Play Process Production Protein Isoforms Protein Kinase Pulmonary Hypertension Pulmonary artery structure Quality Control Reactive Oxygen Species Reporting Research Resolution Respiration Right Ventricular Function Role Severities Signal Pathway Signal Transduction Single Nucleotide Polymorphism Small Interfering RNA Smooth Muscle Myocytes Spectrum Analysis Spirometry Superoxide Dismutase Superoxides Testing Therapeutic Tissues Variant Vascular remodeling Ventricular Wild Type Mouse antioxidant enzyme design extracellular fatty acid oxidation glucose uptake hemodynamics human model hypoxia-induced pulmonary hypertension in vitro testing inhibitor insight mitochondrial dysfunction mouse model novel oxidation pharmacologic premature pulmonary arterial pressure right ventricular failure therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Despite novel treatments, pulmonary hypertension (PH) represents a progressive, highly morbid, and often fatal condition. Recent studies suggest that metabolic derangements such as the glycolytic switch, ROS production, and mitochondrial dysfunction play a key role in the pathogenesis of PH. Disruptions of ROS homeostasis, primarily regulated by the superoxide (SOD) family, have been associated with PH. Extracellular superoxide dismutase (EC-SOD) is the most prevalent isoform of SOD in the vasculature and has been previously associated with PH in mouse models. In humans, the R213G EC-SOD SNP leads to a reduced matrix binding affinity of EC-SOD, leading to low vascular concentration but higher plasma levels and normal activity. In mice, this SNP has been associated with higher right ventricular pressures at baseline that worsen with hypoxia. Interestingly, these same mice are protected against PH in the Sugen-hypoxia model. We hypothesize that the redistribution of R213G variant of EC-SOD due to its reduced binding affinity will have discrepant effects depending on the model of PH and this effect will be due to distinct model-dependent activation of AMPK and mitochondrial dysfunction in endothelial cells (PAEC) vs. smooth muscle cells (PASMC). Preliminary data demonstrated that at baseline, mice with the R213G EC-SOD variant have significant differences in lung and right ventricular (RV) fatty acid oxidation and electron transport chain activity. To test the effects of loss of vascular EC-SOD in PH, mice with the R213G EC-SOD SNP will be exposed to chronic hypoxia or Sugen-hypoxia to develop pulmonary hypertension, confirmed via invasive hemodynamic and histologic measures (Aim 1). Mitochondrial respiration and ROS production will be measured by high- resolution respirometry and electron paramagnetic resonance, respectively, in whole lung and RV homogenates as well as human pulmonary artery endothelial and smooth muscle cells (Aim 2).

项目摘要/摘要尽管治疗新颖，肺动脉高压（PH）代表了一种进行性，高病态，并且通常是致命状况。最近的研究表明，糖酵解开关诸如ROS之类的代谢异常生产和线粒体功能障碍在pH的发病机理中起关键作用。 ROS的破坏主要受超氧化物（SOD）家族调节的稳态与pH有关。细胞外超氧化物歧化酶（EC-SOD）是脉管系统中SOD最普遍的同工型，并且具有以前与鼠标模型中的pH相关。在人类中，R213G EC-SOD SNP导致 EC-SOD的基质结合亲和力降低，导致血管浓度较低，但血浆水平较高，并且正常活动。在小鼠中，该SNP与基线时较高的右心压有关缺氧恶化。有趣的是，这些相同的小鼠在Sugen-Hypoxia模型中受到pH的保护。我们假设R213G EC-SOD变体的重新分布由于其结合亲和力的降低将具有差异效应取决于pH模型，而这种效果将归因于不同的模型依赖性内皮细胞中AMPK和线粒体功能障碍的激活（PAEC）与平滑肌细胞（PASMC）。初步数据表明，在基线时，具有R213G EC-SOD变体的小鼠具有肺和右心（RV）脂肪酸氧化和电子传输链活性的显着差异。为了测试pH中血管-SOD损失的影响，将暴露于R213G EC-SOD SNP的小鼠暴露于慢性缺氧或Sugen-Hypoxia以浸润性血液动力学证实和组织学措施（AIM 1）。线粒体呼吸和ROS产生将通过高分辨率呼吸测定法和电子顺磁共振共振在整个肺和RV中匀浆以及人类肺动脉内皮和平滑肌细胞（AIM 2）。