Reactive Inflammatory Species in Heart Failure

心力衰竭中的反应性炎症物质

• 批准号: 6951216
• 负责人: Pamela A Lucchesi
• 金额: $ 28.4万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951216
• 关键词: biochemistry; cardiac myocytes; disease /disorder model; echocardiography; electron spin resonance spectroscopy; enzyme activity; extracellular matrix; fibroblasts; free radical oxygen; genetically modified animals; heart failure; heart ventricle; hemodynamics; immunocytochemistry; intracardiac pressure; intracardiac volume; laboratory mouse; laboratory rat; metalloendopeptidases; microdialysis; myeloperoxidase; nitrogen compounds; oxidative stress; pathologic process; proteomics; superoxide dismutase; video microscopy

DESCRIPTION (provided by applicant): In hearts with volume overload, a complex sequence of compensatory events result in a continual state of extra cellular matrix (ECM) remodeling and by changes in myocyte function and eventually leads to congestive heart failure (HF). Increasing evidence suggests that reactive oxygen (ROS) and nitrogen (RNS) species, collectively termed reactive inflammatory species (RIS), and the enzymes that regulate their bioavailability are associated with contractile failure and myocardial structural damage in end-stage HF models. However, the relationship between RIS and the temporal progression of HF has not been extensively studied. Using an aortocaval fistula (ACF) model in the rat, 3 key, clinically relevant, time points in the temporal progression of volume overload have been rigorously defined in vivo: acute (2-5 days), chronic compensated (4-8 weeks), and chronic decompensated (15-21 weeks). Preliminary studies indicate increased tyrosine nitration of myofilament proteins, matrix degrading enzymes and signaling molecules during the acute phase of HF. An imbalance between RIS generating enzymes and antioxidant defenses was also observed acute stage and during the transition to decompensated HF. Moreover, we have found that RIS cause contractile dysfunction in isolated adult cardiac myocytes. This led to the hypothesis that RIS are important mediators of adverse LV remodeling and contractile dysfunction that underlie the development and progression of volume overload-induced HF. Aim 1 will establish a link between reactive inflammatory species and the development and progression of volume overload-induced CHF. RIS will be measured using a combination of microdialysis, ESR (electron spin resonance) and standard biochemical assays. A series of pharmacological interventions and transgenic approaches (iNOS(-/-), myeloperoxidase (-/-), SOD overexpressors) will be used to manipulate RIS levels in vivo. A proteomics approach will used to identify RIS-modulated proteins. Aim 2 will determine the mechanisms by which RIS contribute to LV remodeling in ACF-induced HF, with particular focus on ECM turnover in vivo and the regulation matrix metalloproteinase (MMP) activation by cardiac fibroblasts in vitro. Aim 3 will use video edge microscopy, fluorescent Ca 2+ imaging and immunocytochemistry to determine whether altered susceptibility to RIS during HF progression contributes to cardiomyocyte. The proposed investigations are fundamentally important to the development of therapeutic strategies targeted to oxidant-induced injury and may have important implications in the treatment of HF.

描述（由申请人提供）：在容量超负荷心脏中，一系列复杂的代偿事件导致细胞外基质（ECM）重塑的持续状态和肌细胞功能的变化，最终导致充血性心力衰竭（HF）。越来越多的证据表明，活性氧（ROS）和氮（RNS）物种，统称为反应性炎症物种（RIS），和酶，调节其生物利用度与收缩失败和心肌结构损伤的终末期HF模型。然而，RIS和HF的时间进展之间的关系尚未得到广泛研究。使用大鼠下腔静脉瘘（ACF）模型，在体内严格定义了容量超负荷时间进展的3个关键、临床相关时间点：急性（2-5天）、慢性代偿期（4-8周）和慢性失代偿期（15-21周）。初步研究表明，在心力衰竭急性期，肌丝蛋白、基质降解酶和信号分子的酪氨酸硝化增加。在急性期和向失代偿性HF过渡期间也观察到RIS生成酶和抗氧化防御之间的不平衡。此外，我们还发现RIS可引起离体成人心肌细胞收缩功能障碍。这导致了这样的假设，即RIS是不利的LV重构和收缩功能障碍的重要介质，是容量超负荷诱导的HF的发展和进展的基础。目的1将建立反应性炎症物质与容量超负荷诱导的CHF的发展和进展之间的联系。将使用微透析、ESR（电子自旋共振）和标准生化测定的组合测量RIS。将使用一系列药物干预和转基因方法（iNOS（-/-）、髓过氧化物酶（-/-）、SOD过表达子）来操纵体内RIS水平。蛋白质组学方法将用于鉴定RIS调节的蛋白质。目的2将确定RIS在ACF诱导的HF中促进LV重构的机制，特别关注ECM在体内的更新和心脏成纤维细胞在体外对基质金属蛋白酶（MMP）活化的调节。目的3将使用视频边缘显微镜、荧光钙成像和免疫细胞化学来确定HF进展过程中对RIS敏感性的改变是否有助于心肌细胞。拟议的调查是从根本上重要的针对氧化剂诱导的损伤的治疗策略的发展，并可能有重要的影响，在治疗HF。