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

• 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
• 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

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.

项目摘要 右心（RV）衰竭是肺动脉高压（PAH）死亡的主要原因，是一个 在其他形式的肺动脉高压中导致发病率和死亡率的重要原因。因此，治疗 将鼓励成功适应压力超负荷的RV会延长患者的寿命。目前，没有 存在保留RV功能的批准疗法。血栓烷/前列腺素体受体（TPR）上调 PAH患者的RV心肌细胞和异前列腺，TPR的配体的异丙烷，在心脏中增加 由于氧化应激增加而引起的应变和PAH。 TPR的激活通常是纤维性的，我们有 以前发现，对TPR的药理抑制可防止RV纤维化并改善A中的功能 RV压力超负荷的肺动脉带（PAB）模型。但是，关于 发生这种情况的机制。根据我们以前的研究，TPR拮抗剂Ifetroban计划 全身性硬化症患者的临床试验；了解TPR在PAH期间RV中的作用是 对拮抗剂药物的临床使用至关重要，以及确定其对其他的更广泛适用性 疾病。因此，我们的两个目的提出了测试心肌细胞中TPR激活的假设 通过钙介导 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和 确定是否可以通过遗传或 TPR功能的药理抑制。我们将确定心肌细胞中的TPR激活是否是 与全球TPR敲除相比，具有心肌细胞特异性TPR敲除的这些作用足以满足这些影响。 我们还将在治疗研究中确定TPR激活的促纤维化和/或功能效应是 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该机制 TPR激活在压力超负荷过程中导致纤维化。通过PAB以及一个体外模型 心肌细胞菌株，我们将从G蛋白耦合TPR中描述信号事件并检验假设 心肌细胞中持续的TPR依赖性钙信号传导会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 成纤维细胞以及成纤维细胞TPR的任何贡献。纤维化和功能变化的交集 心中很复杂，这项研究还将有助于定义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，有助于纤维化。 这项研究的总体结果将描述TPR在压力超负荷过程中的RV中的作用，并且 确定TPR拮抗剂作为支持RV适应PAH的治疗的功效，并预测其 用于其他应用程序。