Determinants of Right Heart Failure In Severe PAH

肺动脉高压导致右室(RV)慢性压力超负荷，这总是 导致右室肥厚(RVF)。失代偿性心脏衰竭(RHF) 对压力超负荷的肥大反应是重症高血压患者死亡的主要原因 肺动脉高压(SPH)。然而，尽管它具有深远的临床后果，但人们对它知之甚少。 自发性高血压患者的右室适应和衰竭。我们提出了一种综合的生理学、 用细胞和分子方法确定肺性心衰动物模型中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组织 与人类SPH和引起RV相关的血管变化，很少会导致RHF。我们证明了 慢性缺氧和阻断血管内皮生长因子受体导致RVH进展为收缩 心力衰竭典型的功能障碍和适应不良重构，而慢性低氧本身就会产生稳定的RVH 也没有RHF。此外，将血管内皮生长因子受体阻断应用于纯血流动力学应激(肺 动脉环扎术)恶化右室功能。由这些操作触发的RVF与 降低NO的生物利用度和cGMP/PKG-1信号通路的改变从而降低其 抑制肥大和增强血管内皮细胞生长因子信号的有效性。重新激活cGMP/PKG-1 通过慢性抑制cGMP特异性磷酸二酯酶5A(PDE5AI)的信号转导 低氧/血管内皮细胞生长因子受体阻断模型中的“病理性”肥大反应更接近于 “生理性”肥大，胎儿心脏基因程序被抑制，心肌细胞生长 有限的。根据这些初步数据，我们推测，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 对不利的血流动力学和/或神经应激的反应。这一信号轴的破坏 而心肌细胞和内皮细胞之间的细胞间通讯导致 失代偿、适应不良的重塑和心力衰竭。具体目标#1将决定是否 PAH引起的血流动力学应激加上血管内皮生长因子受体阻断导致从 自适应RVH到RVF。具体目标#2将确定是否由于VEGF/NO/GMP信号的中断 潜在的氧化应激导致右心的不适应性重塑和转变 致RVF。具体目标#3将确定RVF在肺环境中的新的遗传修饰物 利用共生大鼠品系作为遗传分析平台的高血压。对……作用的理解 RHF中血管内皮生长因子/NO/cGMP信号转导途径及影响RHF易感性的QTL的发现 这种功能障碍是开发预防PAH相关RVF的基本疗法的关键一步。项目 5将与项目4高度集成，并将提供对房车机制的机械性见解 功能障碍(项目2)和项目1和3的潜在生物标记物。

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.