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Role of the thromboxane prostanoid receptor in right ventricular adaptation to pressure overload

血栓素前列腺素受体在右心室压力超负荷适应中的作用

基本信息

批准号：
10183297
负责人：
Erica J Carrier
金额：
$ 44.04万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183297
关键词：
Address Affect Aspirin Biological Availability Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium Signaling Cardiac Cardiac Myocytes Cause of Death Cells Chronic Clinical Clinical Trials Coculture Techniques Complex Coupled Disease Drug Antagonism Event Failure Fibroblasts Fibrosis Functional disorder GTP-Binding Proteins Genetic Goals Heart Heart failure Human Hypoxia Immune Intervention Isoprostanes Knock-out Knockout Mice Lead Life Ligands Lung Mediating Mediator of activation protein Modeling Morbidity - disease rate Mus Myocardial dysfunction Myofibroblast Oxidative Stress Pathologic Pathway interactions Patient-Focused Outcomes Patients Peptide Receptor Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Physiologic intraventricular pressure Physiology Production Prostaglandins Proteins Pulmonary Hypertension Pulmonary artery structure Receptor Activation Receptor Inhibition Receptor Signaling Right Ventricular Function Role Safety Signal Transduction Specificity Stress Systemic Scleroderma Testing Thrombosis Thromboxane Receptor Thromboxanes Translations Trichrome stain Ventricular Wild Type Mouse antagonist G base calmodulin-dependent protein kinase II cell type coronary fibrosis druggable target follow-up functional adaptation functional decline functional disability heart function heart preservation ifetroban improved improved functioning improved outcome in vitro Model in vivo inhibitor/antagonist mortality mouse model novel pre-clinical research preservation pressure prevent primary pulmonary hypertension pulmonary arterial hypertension receptor receptor function response treatment strategy

项目摘要

PROJECT SUMMARY Right ventricular (RV) failure is the primary cause of death in pulmonary arterial hypertension (PAH), and is a significant cause of morbidity and mortality in other forms of pulmonary hypertension. Therefore, treatment that would encourage successful RV adaptation to pressure overload would prolong patient life. Currently, no approved therapies exist that preserve RV function. The thromboxane/prostanoid receptor (TPr) is upregulated on RV cardiomyocytes in PAH patients, and isoprostanes, ligands of the TPr, are increased during cardiac strain and PAH due to increased oxidative stress. Activation of the TPr is generally pro-fibrotic, and we have previously found that pharmacologic inhibition of the TPr prevents RV fibrosis and improves function in a pulmonary artery banding (PAB) model of RV pressure overload. However, little is known about the mechanism by which this occurs. Based on our previous studies, the TPr antagonist ifetroban is slated for a clinical trial in systemic sclerosis patients with PAH; understanding the role of the TPr in the RV during PAH is critical to the clinical use of antagonist drugs as well as to determining their broader applicability to other diseases. Therefore, our two aims propose to test the hypothesis that TPr activation in cardiomyocytes drives the RV fibrotic response, and resulting decline in RV function during pressure overload, via calcium-mediated signaling. Using PAB to directly induce RV pressure overload, we will follow up our antagonist studies and determine whether fibrosis and the functional effects of RV pressure overload can be reversed via genetic or pharmacologic inhibition of TPr function. We will ascertain whether TPr activation in cardiomyocytes is sufficient for these effects with a cardiomyocyte-specific TPr knockout, compared with a global TPr knockout. We will also determine in a treatment study whether the pro-fibrotic and/or functional effects of TPr activation in this PAH model can be reversed with TPr antagonism. Our next goal is to determine the mechanism by which TPr activation causes fibrosis during pressure overload. Through PAB as well as an in vitro model of cardiomyocyte strain, we will delineate signaling events from the G-protein coupled TPr and test the hypothesis that sustained TPr-dependent calcium signaling in cardiomyocytes causes cellular dysfunction and alters their interaction with non-myocytes. We will examine how cardiomyocyte TPr activation affects surrounding fibroblasts, as well as any contribution from a fibroblast TPr. The intersection of fibrosis and functional changes in the heart are complex, and this study will also aid in the definition of signaling events from the TPr that contribute to fibrosis, compared with changes in contractile function, at both a cellular and whole heart level. The overall results of this study will delineate the role of the TPr in the RV during pressure overload, and determine the efficacy of a TPr antagonist as treatment supporting RV adaptation in PAH, as well as predict its use for other applications.

项目概要右心室（RV）衰竭是肺动脉高压（PAH）死亡的主要原因，也是肺动脉高压（PAH）患者死亡的主要原因。是其他形式肺动脉高压发病和死亡的重要原因。因此，治疗将鼓励 RV 成功适应压力过载，从而延长患者的生命。目前，没有存在已批准的保留右心室功能的疗法。血栓素/前列腺素受体 (TPr) 上调 PAH 患者的 RV 心肌细胞中的 TPR 配体异前列素在心脏过程中增加氧化应激增加导致的应变和 PAH。 TPR 的激活通常是促纤维化的，我们有先前发现，TPr 的药物抑制可预防 RV 纤维化并改善右室功能右心室压力超负荷的肺动脉束带（PAB）模型。然而，人们对此知之甚少发生这种情况的机制。根据我们之前的研究，TPr 拮抗剂伊非曲班预计将用于系统性硬化症 PAH 患者的临床试验；了解 PAH 期间 RV 中 TPR 的作用是对于拮抗剂药物的临床使用以及确定其更广泛的适用性至关重要疾病。因此，我们的两个目标是检验心肌细胞中 Tpr 激活驱动的假设通过钙介导的 RV 纤维化反应，以及压力超负荷期间导致的 RV 功能下降发信号。使用 PAB 直接诱导 RV 压力超负荷，我们将跟进我们的拮抗剂研究并确定纤维化和右心室压力超负荷的功能影响是否可以通过遗传或药理抑制TPr功能。我们将确定心肌细胞中的 Tpr 激活是否与整体 TPR 敲除相比，心肌细胞特异性 TPR 敲除足以产生这些效果。我们还将在治疗研究中确定 TPR 激活是否对纤维化和/或功能产生影响。这种PAH模型可以通过TPr拮抗作用逆转。我们的下一个目标是确定一种机制 Tpr 激活在压力超负荷期间导致纤维化。通过 PAB 以及体外模型心肌细胞株，我们将描述 G 蛋白偶联 Tpr 的信号传导事件并检验假设心肌细胞中持续的 TPR 依赖性钙信号传导导致细胞功能障碍并改变其与非肌细胞的相互作用。我们将研究心肌细胞 Tpr 激活如何影响周围环境成纤维细胞，以及来自成纤维细胞TPr的任何贡献。纤维化和功能变化的交叉点心脏中的信号事件很复杂，这项研究还将有助于定义来自 TPR 的信号事件，与收缩功能的变化相比，在细胞和整个心脏水平上都会导致纤维化。这项研究的总体结果将描述压力超负荷期间 RV 中 TPr 的作用，以及确定 Tpr 拮抗剂作为支持 PAH RV 适应治疗的疗效，并预测其效果用于其他应用程序。