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，始终 导致右心肥大（RVF）。右心衰竭（RHF）由代偿不足引起 对压力超负荷的肥厚反应是严重患者的主要死亡原因 肺动脉高压（SPH）。尽管有深远的临床后果，但对 SPH背景下的右心室适应和失败。我们提出了一个综合的生理学， 细胞和分子方法，用于识别肺部动物模型中RHF的决定因素 高血压。虽然许多肺动脉高压的动物模型模仿了一些肺部 与人类SPH相关的血管变化并导致RV），很少会导致RHF。我们表明 将慢性缺氧与VEGF受体阻滞结合起来导致RVH发展为收缩 HF的功能障碍和不良适应性重塑，而仅慢性缺氧就会产生稳定的RVH 而且没有RHF。另外，将VEGF受体阻滞剂应用于纯血液动力应激（肺部） 动脉带）恶化RV功能。这些操作触发的RVF与 降低了CGMP/PKG-1信号传导途径的任何生物利用度和改变的变化 抑制肥大和增强VEGF信号的有效性。重新激活CGMP/PKG-1 通过慢性抑制CGMP特异性磷酸二酯酶5A（PDE5AI）的信号传导会改变 缺氧/VEGFR2阻断模型中的“病理”肥厚反应更紧密地匹配 “生理”肥大，其中抑制胎儿心脏基因程序，心肌细胞的生长是 有限的。基于这些初步数据，我们假设VEGF/NO/CGMP信号轴 协调成人心脏（肥大）的生长以产生稳定的分子和细胞 对不良血液动力学和/或神经hp症应力的反应。该信号轴的破坏 心肌细胞和内皮细胞之间的细胞间通信导致 代偿性，适应不良的重塑和心力衰竭。特定目标＃1将决定是否 由PAH引起的血液动力学应激与VEGF受体阻滞作用导致从 自适应RVH至RVF。具体目标＃2will确定vegf/no/gmp信号的破坏是否到期 潜在的氧化应激有助于右心的适应不良重塑和过渡 到RVF。特定的目标＃3将在肺部设置中识别RVF的新型遗传修饰符 使用综合大鼠菌株作为遗传分析的平台高血压。理解 RHF中的VEGF/NO/CGMP途径以及识别QTL的QTL，以修改程度或易感性 这种功能障碍是开发原理疗法以防止与PAH相关的RVF的关键步骤。项目 5将与项目4高度融合，并将提供有关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。