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

项目摘要 右心室（RV）衰竭是肺动脉高压（PAH）患者死亡的主要原因，也是一种 是其他形式肺动脉高压发病率和死亡率的重要原因。因此， 鼓励RV成功适应压力超负荷将延长患者生命。当前没有任何 存在保留RV功能的批准的疗法。血栓素/前列腺素受体（TPr）上调 PAH患者的RV心肌细胞上，TPr的配体异前列腺素在心脏过程中增加， 应变和PAH由于增加氧化应激。TPr的激活通常是促纤维化的，我们有 先前发现，TPr的药理学抑制可预防RV纤维化并改善RV功能， 右室压力超负荷的肺动脉缩窄（PAB）模型。然而，人们对此知之甚少。 这种情况发生的机制。基于我们以前的研究，TPr拮抗剂伊非曲班被预定用于治疗。 PAH系统性硬化症患者的临床试验;了解PAH期间RV中TPr的作用， 这对于拮抗剂药物的临床使用以及确定它们对其他药物的更广泛适用性至关重要。 疾病因此，我们的两个目标是检验心肌细胞中TPr激活驱动心肌细胞凋亡的假设。 RV纤维化反应，并导致RV功能下降，在压力超负荷，通过钙介导的 发信号。使用PAB直接诱导RV压力超负荷，我们将随访拮抗剂研究， 确定纤维化和RV压力超负荷的功能效应是否可以通过遗传或 TPr功能的药理学抑制。我们将确定心肌细胞中的TPr激活是否是 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激活在肝纤维化中的促纤维化和/或功能作用是否与TPr激活的肝纤维化有关。 这种PAH模型可以用TPr拮抗作用逆转。我们的下一个目标是确定 TPr激活在压力超负荷期间引起纤维化。通过PAB以及体外模型， 心肌细胞株，我们将描绘信号事件从G蛋白偶联TPr和测试的假设 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，并改变了它们的功能。 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TPr是复杂的，这项研究也将有助于定义来自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， 本研究的总体结果将描述压力超负荷期间TPr在RV中的作用， 确定TPr拮抗剂作为PAH中支持RV适应的治疗的疗效，并预测其 用于其他应用。

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.