Understanding and targeting molecular as well as structural events governing right ventricular adaptation, failure and recovery in pulmonary hypertension using repurposed drugs

使用重新利用的药物了解和靶向控制肺动脉高压右心室适应、衰竭和恢复的分子和结构事件

• 批准号: 10615148
• 负责人: Edda Frauke Spiekerkoetter
• 金额: $ 41.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-25 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615148
• 关键词: 3-Dimensional; Acceleration; Acute; Address; Architecture; Blood Vessels; Blood capillaries; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Chronic; Chronic pulmonary heart disease; Clinical; Clinical Trials; Dependence; Diffusion; Disease; Early identification; Etiology; Event; FK506; Failure; Fibroblasts; Fibrosis; Genetic; Health; Histologic; Human Rights; Hypoxia; Impairment; Ischemia; Knowledge; Left; Life; Link; Liquid substance; Location; Lung; Medical; Microcirculation; Mission; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardial; Nutrient; Oxygen; Pathologic; Pharmaceutical Preparations; Process; Pulmonary Embolism; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Radial; Recovery; Recovery of Function; Research; Right Ventricular Hypertrophy; Right ventricular strain; Right ventricular structure; Risk; Role; Signal Transduction; Snails; Spatial Distribution; Surface; Surgical sutures; Tacrolimus; Testing; Therapeutic; Three-Dimensional Imaging; Tissue imaging; Tissues; United States National Institutes of Health; Ventricular; bone morphogenetic protein receptors; cardiac magnetic resonance imaging; congenital heart disorder; coronary fibrosis; density; disability; drug repurposing; druggable target; heart function; histological studies; improved; mortality; mouse model; novel; novel therapeutics; pressure; prevent; pulmonary arterial hypertension; right ventricular failure; three-dimensional modeling; thrombolysis; tool

Despite the clinical importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH), surprisingly little is known about the molecular and structural mechanisms of RV adaptive and maladaptive remodeling and the transition to RV failure. This is particularly important when the RV is not the primary cause of RV failure, but when a temporary support of the RV would be desirable until the primary cause can be fixed. Approaches that normalize pulmonary vascular resistance (PVR) and reduce RV afterload would improve RV function and reverse RV failure. Unfortunately, no currently available medical therapy is able to significantly reduce PVR long-term in chronic PAH or thromboembolic PH (CTEPH). As RV failure is the most common cause of death in PAH, approaches to support the RV to better adapt to an increased afterload are highly sought after. In this proposal, we will focus on two pathological features that put the RV uniquely at risk for failure: (1) cardiac fibrosis, that reduces RV systolic/diastolic function, disrupts the myocardial architecture, and impairs the exchange of oxygen/nutrients and (2) impaired microvascular adaptation (= capillary rarefaction) that results in RV ischemia. Both are controversially debated as to their role in RV adaptation, failure as well as in recovery. We use a novel mouse model of pulmonary artery banding (PAB) and de-banding (de-PAB) to quantitatively capture histological changes in the RV using 3-D deep tissue imaging and to link them to cardiac function with cardiac MRI (CMR). As a deficiency in Bone morphogenetic protein receptor 2 (BMPR2) signaling is thought to put the RV at risk for failure, we evaluate whether two repurposed drugs, Tacrolimus (FK506) and Enzastaurin, previously shown by our group to increase BMPR2 signaling, assist the RV by reducing cardiac fibrosis and improving vascular adaptation and accelerate recovery. Moreover, we have identified early, RV specific expression of SNAIL1 in cardiac fibroblasts as a promising and druggable target to improved cardiac fibrosis. We hypothesize that Inhibiting Snail and increasing BMPR2 with FK506 and Enzastaurin will reduce cardiac fibrosis, improve capillary density and improve RV function in the pressure overloaded murine RV. Our proposal has three significant parts, which are represented by our three specific aims: First, we will target molecular events that govern RV fibrosis in the pressure overloaded RV with genetic tools and repurposed drugs to improve RV function and strain as assessed by CMR in PAB mice. Second, we will characterize the adaptation of the RV microvasculature in PAB mice and human RV PH tissue, construct a 3- D model of the RV microcirculation to predict how structural changes in the RV influence fluid and diffusion dynamics and third, we will study histological and functional recovery of the RV in a novel de-banding mouse model. By studying and targeting RV adaptation and failure, we not only address the most important cause of mortality in PAH but also help improve other diseases, in which the RV is uniquely at risk for failure such as in chronic lung and left heart disease, CTEPH as well as congenital heart disease.

尽管右心室（RV）在肺动脉高压（PAH）中的临床重要性令人惊讶 关于RV自适应和适应不良重塑的分子和结构机制知之甚少 过渡到RV故障。当RV不是RV故障的主要原因时，这一点尤其重要， 但是，当需要对RV的临时支撑之前，直到可以固定主要原因为止。 将肺血管阻力（PVR）归一化并减少RV后负载的方法将改善RV 功能和反向RV故障。不幸的是，目前没有可用的医疗疗法能够显着 在慢性PAH或血栓栓塞pH（CTEPH）中长期降低PVR。因为RV失败是最常见的 PAH死亡原因，支持RV更好适应增加后负载的方法很高 被）追捧。在此提案中，我们将重点介绍两个病理特征，使RV有独特的风险 故障：（1）心脏纤维化，减少RV收缩/舒张功能，破坏心肌体系结构，并 损害氧气/养分的交换和（2）微血管适应受损（=毛细血管稀有） 这导致了RV缺血。两者都争议就它们在RV适应中的作用，失败也引起争议 就像恢复一样。我们使用一种新型的肺动脉带（PAB）和DE-BAND（DE-PAB）的小鼠模型 使用3-D深组织成像定量捕获RV中的组织学变化，并将其链接到心脏 通过心脏MRI（CMR）功能。作为骨形态发生蛋白受体2（BMPR2）信号的缺乏 人们认为将房车置于失败的风险中，我们评估了两种再利用药物，他克莫司（FK506） 和Enzastaurin，以前由我们的组提高以增加BMPR2信号传导，通过还原来帮助RV 心脏纤维化并改善血管适应并加速恢复。而且，我们已经提早确定 心脏成纤维细胞中Snail1的RV比表达特异性表达是改进的有希望的可药物靶标 心脏纤维化。我们假设用FK506抑制蜗牛并增加BMPR2，Enzastaurin将会 减少心脏纤维化，改善毛细管密度并改善压力超载的RV功能 RV。我们的建议有三个重要部分，这些部分由我们的三个具体目标表示：首先，我们将 靶向分子事件，该事件在压力超载RV中使用遗传工具和 通过CMR在PAB小鼠中评估的RV功能和应变，以改善RV功能和应变。第二，我们会的 表征PAB小鼠和人RV pH组织中RV微脉管系统的适应 RV微循环的D模型，以预测RV的结构变化如何影响流体和扩散 动力学和第三，我们将研究新型De带小鼠中RV的组织学和功能恢复 模型。通过研究和定位RV的适应和失败，我们不仅要解决最重要的 PAH死亡率的原因，但也有助于改善其他疾病，其中RV有独特的风险 失败，例如在慢性肺和左心脏病，CTEPH以及先天性心脏病。

项目成果

Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.

• DOI: 10.1186/s12968-021-00759-8
• 发表时间: 2021-06-03
• 期刊: Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
• 作者: Dufva MJ;Boehm M;Ichimura K;Truong U;Qin X;Tabakh J;Hunter KS;Ivy D;Spiekerkoetter E;Kheyfets VO
• 通讯作者: Kheyfets VO

Shunt-type plexiform lesions identified in the Sugen5416/hypoxia rat model of pulmonary arterial hypertension using synchrotron-based phase-contrast micro-CT.

• DOI: 10.1183/13993003.02802-2021
• 发表时间: 2022-06
• 期刊: The European respiratory journal