Determinants of Right Heart Failure In Severe PAH

严重肺动脉高压患者右心衰竭的决定因素

• 批准号: 8013840
• 负责人: MICHAEL T CROW
• 金额: $ 40.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013840
• 关键词: 3-nitrotyrosine; Adult; Affect; Animal Model; Animals; Arteries; Arts; Biological Availability; Biological Markers; Blood Vessels; Blood capillaries; Calcium; Cardiac; Cardiac Myocytes; Cardiac Output; Cause of Death; Chromosomes; Chronic; Clinical; Collaborations; Consomic Strain; Coupled; Coupling; Cyclic GMP; Data; Development; Distal; Effectiveness; Endothelial Cells; Exposure to; Extracellular Matrix; Failure; Fibrosis; Functional disorder; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Homeostasis; Human; Human Resources; Hypertrophy; Hypoxia; Individual; Left ventricular structure; Lesion; Lung; Medial; Microfilaments; Modeling; Molecular; Molecular Profiling; Muscle Cells; Myocardial; NOS3 gene; Nature; Norway; Oral; Oxidative Stress; Pathway interactions; Patients; Performance; Peripheral; Physiological; Population; Predisposition; Preventive; Production; Proteomics; Pulmonary Hypertension; Pulmonary artery structure; Quantitative Trait Loci; Rat Strains; Rattus; Reactive Oxygen Species; Receptor Signaling; Reporting; Research Personnel; Right Ventricular Dysfunction; Right Ventricular Hypertrophy; Right ventricular structure; Right-On; Rodent Model; Role; Signal Pathway; Signal Transduction; Source; Staging; Stress; Surveys; Testing; Therapeutic; Time; Tissues; Transcript; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular remodeling; Ventricular; Ventricular Remodeling; base; capillary; consomic; dimer; fetal; genetic analysis; genome-wide; hemodynamics; human NOS3 protein; inhibitor/antagonist; insight; intercellular communication; novel; phosphodiesterase V; phosphoric diester hydrolase; pressure; prevent; programs; pulmonary arterial hypertension; release of sequestered calcium ion into cytoplasm; resistant strain; response; salt sensitive; sildenafil; stressor; tetrahydrobiopterin

Pulmonary hypertension results in chronic pressure overload of the right ventricle (RV), which invariably results in right ventricular hypertrophy (RVF). Right heart failure (RHF) caused by a decompensated hypertrophic response to pressure overload is the leading cause of death in patients with severe pulmonary hypertension (SPH). Despite its profound clinical consequences, however, little is known about right ventricular adaptation and failure within the context of SPH. We propose an integrated physiological, cellular, and molecular approach to identifying the determinants of RHF in animal models of pulmonary hypertension. While many animal models of pulmonary hypertension mimic some of the pulmonary vascular changes associated with the human SPH and cause RV), few result in RHF. We show that combining chronic hypoxia with VEGF receptor blockade results in RVH that progresses to contractile dysfunction and maladaptive remodeling typical of HF, while chronic hypoxia alone produces a stable RVH and no RHF. In addition, applying VEGF receptor blockade to a pure hemodynamic stress (pulmonary artery banding) worsens RV function. The RVF triggered by these manipulations is associated with decreased NO bioavailability and alterations in the cGMP/PKG-1 signaling pathway that decrease its effectiveness in suppressing hypertrophy and potentiating VEGF signaling. Reactivating cGMP/PKG-1 signaling through chronic inhibition of the cGMP-specific phosphodiesterase 5A (PDE5AI) transforms the "pathological" hypertrophic response in the hypoxia/VEGFR2 blockade model to more closely match that of "physiological" hypertrophy, in which the fetal cardiac gene program is suppressed and myocyte growth is limited. Based on these preliminary data, we hypothesize that the VEGF/NO/cGMP signaling axis coordinates the growth of the adult heart (hypertrophy) to produce a stable molecular and cellular response to adverse hemodynamic and/or neurohprmonal stress. Disruption of this signaling axis and the intercellular communication between cardiac myocytes and endothelial cells leads to decompensation, maladaptive remodeling, and heart failure. Specific Aim #1 will determine whether hemodynamic stress caused by PAH coupled with VEGF receptor blockade causes the transition from adaptive RVH to RVF. Specific Aim #2will determine whether disruption of VEGF/NO/GMP signaling due to underlying oxidative stress contributes to the maladaptive remodeling of the right heart and the transition to RVF. Specific Aim #3 will identify novel genetic modifiers of RVF in the setting of pulmonary hypertension using consomic rat strains as a platform for genetic analysis. An understanding of the role of VEGF/NO/cGMP pathway in RHF and the identification of QTLs that modify the extent or susceptibility to such dysfunction is a critical step in developing rationale therapies to prevent PAH-associated RVF. Project 5 will be highly integrated with Project 4, and will provide mechanistic insights into mechanisms of RV dysfunction (Project 2) and potential biomarkers for Projects 1 and 3.

肺动脉高压导致右心室（RV）的慢性压力超负荷， 导致右心室肥大（RVF）。右心衰竭（RHF）由失代偿性 对压力超负荷的肥大反应是重度脑梗死患者死亡的主要原因。 肺动脉高压（SPH）。尽管其临床后果深远，然而， SPH背景下的右心室适应和衰竭。我们提出了一个综合的生理， 细胞和分子的方法来确定RHF的决定因素，在动物模型的肺 高血压虽然许多肺动脉高压的动物模型模拟了一些肺动脉高压， 与人类SPH相关的血管变化并导致RV），很少导致RHF。我们证明了 慢性缺氧结合VEGF受体阻断导致RVH进展为收缩性 HF典型的功能障碍和适应不良重塑，而慢性缺氧单独产生稳定的RVH 没有RHF。此外，将VEGF受体阻断剂应用于纯血流动力学应激（肺动脉高压）， 动脉束带）影响RV功能。这些操纵所引发的裂谷热与下列因素有关： NO生物利用度降低，cGMP/PKG-1信号通路改变， 有效抑制肥大和增强VEGF信号传导。重新激活cGMP/PKG-1 通过慢性抑制cGMP特异性磷酸二酯酶5A（PDE 5AI）的信号传导将cGMP特异性磷酸二酯酶5A（PDE 5AI）转化为磷酸二酯酶5A。 缺氧/VEGFR 2阻断模型中的“病理性”肥大反应，以更接近地匹配缺氧/VEGFR 2阻断模型中的“病理性”肥大反应。 “生理性”肥大，其中胎儿心脏基因程序受到抑制，肌细胞生长受到抑制。 有限公司基于这些初步数据，我们假设VEGF/NO/cGMP信号轴 协调成人心脏的生长（肥大），以产生稳定的分子和细胞 对不利的血液动力学和/或神经压力的反应。这个信号轴的中断 心肌细胞和内皮细胞之间的细胞间通讯导致 失代偿、适应不良重塑和心力衰竭。具体目标#1将决定是否 PAH引起的血流动力学应激与VEGF受体阻滞剂联合作用， 适应性RVH到RVF。具体目标#2将确定VEGF/NO/GMP信号转导的破坏是否由于 潜在的氧化应激导致右心适应不良的重塑， 到裂谷热。具体目标#3将在肺部环境中识别RVF的新型遗传修饰剂 高血压使用conomic大鼠品系作为遗传分析的平台。对《公约》作用的理解 RHF中VEGF/NO/cGMP通路的研究以及改变RHF的程度或易感性的QTL的鉴定 这种功能障碍是开发预防PAH相关裂谷热的合理疗法的关键步骤。项目 5将与项目4高度集成，并将提供对RV机制的机械见解 功能障碍（项目2）和项目1和3的潜在生物标志物。