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Reactive oxygen species and respiratory muscle dysfunction in heart failure

Reactive oxygen species and respiratory muscle dysfunction in heart failure
心力衰竭中的活性氧和呼吸肌功能障碍
批准号:
9005398
负责人:
Leonardo Ferreira
金额:
$37.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-01-01 至 2020-12-31

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中文摘要
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英文摘要
 DESCRIPTION (provided by applicant): Diaphragm weakness is a significant health problem in chronic heart failure (CHF) patients because: a) compromises their ability to sustain ventilation and limits physical activity due to dyspnea, b) triggers sympathetic activation that ca lead to cardiac arrhythmias and death or induces vasoconstriction and fatigue in limb muscles, and c) impairs airway clearance, predisposing patients to pneumonia. These observations highlight the importance of understanding the mechanisms underlying diaphragm abnormalities and the need to identify biological targets for prevention of weakness in CHF. CHF diaphragm weakness is predominantly caused by loss of specific force (i.e. contractile dysfunction) due to alterations in myofibrillar proteins, and reactive oxygen species (ROS) have been implicated in this process. The mitochondria electron transport chain has been considered the main source of ROS in muscle. However, our preliminary data from human diaphragm biopsies and animal models suggest that NADPH oxidases (Nox) localized predominantly in diaphragm sarcolemma (Nox2) and mitochondria (Nox4) are involved in the heightened ROS and diaphragm weakness in CHF. Moreover, our pilot studies suggest that myofibrillar protein thiol oxidation is a key molecular event in CHF induced diaphragm weakness. Based on our data, we propose to complete three specific aims: 1) to determine the role of diaphragmatic Nox2 complex on excess ROS and weakness in CHF, 2) to determine whether Nox4 and mitochondrial ROS are mediators of diaphragm weakness in CHF, 3) to define the mechanism of ROS-induced diaphragm contractile dysfunction in CHF. To address these aims, we will use inducible skeletal muscle specific knockout mice and intra-pleural injection of recombinant adeno-associated virus with shRNA or expression plasmids under control of a skeletal muscle-specific promoter to target diaphragm fibers in Sham and CHF mice. We will also isolate diaphragm single fibers from sham and CHF mice and perform experiments to determine if specific force deficits can be rescued in vitro. Finally, we will use global label free proteomics and differential Cysteine labeling to determine the abundance of proteins and redox status of specific Cysteine residues in diaphragm from Sham and CHF animals. Our focus on ROS sources, molecular species and targets, and reversibility is critical to understand the pathophysiology and set the stage for nove therapies to treat diaphragm weakness that contributes to the morbidity and mortality in CHF patients.
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Systemic antioxidant treatment for cardiomyopathy, muscle weakness, and exercise intolerance in postmenopausal HFpEF
  • 批准号:
    10593536
  • 项目类别:
  • 资助金额:
    $22.88万
  • 财政年份:
    2022
  • 负责人:
    Leonardo Ferreira
  • 依托单位:
Reactive Oxygen Species and Respiratory Muscle Dysfunction in Heart Failure
  • 批准号:
    10643945
  • 项目类别:
  • 资助金额:
    $3.9万
  • 财政年份:
    2016
  • 负责人:
    Leonardo Ferreira
  • 依托单位:
Reactive Oxygen Species and Respiratory Muscle Dysfunction in Heart Failure
  • 批准号:
    10440819
  • 项目类别:
  • 资助金额:
    $43.62万
  • 财政年份:
    2016
  • 负责人:
    Leonardo Ferreira
  • 依托单位:
Mechanisms of reduced regenerative potential in aging skeletal muscle
  • 批准号:
    8443387
  • 项目类别:
  • 资助金额:
    $6.92万
  • 财政年份:
    2012
  • 负责人:
    Leonardo Ferreira
  • 依托单位:
海外基金