The role of xanthine oxidoreductase activity and altered metabolism in scleroderma-associated pulmonary arterial hypertension

项目摘要/摘要 肺动脉高压(PAH)是一种进行性的肺血管疾病，导致右 心力衰竭和死亡。硬皮病(SSC)患者患PAH(SSC-PAH)的风险很高， 这是导致SSC死亡的主要原因。虽然PAH疗法的进步导致了结果的改善， SSc-PAH的存活率仍然很低，57%的患者在确诊后5年内死亡。因此，有一个 迫切需要扩大SSc-PAH的治疗选择，并确定疾病风险和严重程度的新标记物。 PAH的发病机制非常复杂，同时存在多条生物通路的失调，但目前 PAH的治疗只针对调节血管舒缩张力的三条途径。一种潜在的靶向代谢 调节因子是蛋白质黄嘌呤氧化还原酶(XOR)，它在酶促反应中代谢嘌呤， 产生尿酸和活性氧(ROS)。过量的ROS驱动引起的氧化损伤 血管内皮细胞功能障碍、代谢信号改变和内皮细胞凋亡，这些都是PAH的早期特征 病理生物学。实验性PH模型中XOR活性增加，用别嘌醇抑制XOR可防止 发生肺动脉高压改变。与健康人相比，PAH患者的XOR活性增加 对照，我们的初步数据显示，血清UA/XOR水平和嘌呤代谢产物显著相关 对SSc-PAH患者的血流动力学和预后进行预测。然而，XOR还没有被作为驱动程序进行研究 SSc-PAH的疾病和潜在的治疗靶点。 我们假设，XOR活性的增加有助于SSc中PAH的发展并驱动疾病 通过氧化损伤和新陈代谢改变而进展。通过利用两个丰富的数据源-世界上 已知最大的SSC血清生物库，以及由NIH赞助的新诊断的SSC-PAH的预期队列 患者-我们的目标是1)证明XOR活性增加和氧化应激影响 硬皮病患者中的PAH，2)将XOR活性和氧化应激与表型和预后数据联系起来 SSC-PAH(特别关注右室结构和功能表型)，以及3)识别代谢 与目前可用的PAH疗法临床反应差相关的模式。这些目标将检验 XOR活性和氧化应激在SSc-PAH中的作用以阐明XOR的治疗潜力 为在SSC中个体化选择PAH疗法奠定基础。

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right heart failure and death. Patients with scleroderma (SSc) are at high risk for the development of PAH (SSc-PAH), which is a leading cause of death in SSc. While advances in PAH therapeutics have led to improved outcomes, survival in SSc-PAH remains dismal, with 57% of patients dying within 5 years of diagnosis. Thus, there is an urgent need to expand therapeutic options in SSc-PAH, and to identify novel markers of disease risk and severity. PAH pathogenesis is highly complex, with simultaneous dysregulation of multiple biologic pathways, yet current therapies for PAH target just three pathways that regulate vasomotor tone. One potentially targetable metabolic regulator is the protein xanthine oxidoreductase (XOR), which metabolizes purines in an enzymatic reaction that generates uric acid and reactive oxygen species (ROS). Oxidative injury from over-abundant ROS drives endothelial cell dysfunction, altered metabolic signaling, and endothelial apoptosis, all early features of PAH pathobiology. XOR activity increases in experimental PH models, and XOR inhibition with allopurinol prevents pulmonary hypertensive changes from occurring. XOR activity is increased in PAH patients compared to healthy controls, and our preliminary data show that serum UA/XOR levels and purine metabolites significantly correlate with hemodynamics and predict outcomes in SSc-PAH patients. However, XOR has not been studied as a driver of disease and potential therapeutic target in SSc-PAH. We hypothesize that increased XOR activity contributes to PAH development in SSc and drives disease progression through oxidative injury and altered metabolism. By leveraging two rich data sources – the world's largest known SSc serum biorepository, and an NIH-sponsored prospective cohort of newly diagnosed SSc-PAH patients - we aim to 1) demonstrate that increased XOR activity and oxidative stress influence development of PAH in patients with scleroderma, 2) link XOR activity and oxidative stress with phenotypic and outcome data in SSc-PAH (with a special focus on right ventricular structural and functional phenotypes), and 3) identify metabolic patterns associated with poor clinical response to currently available PAH therapies. These aims will examine the role of XOR activity and oxidative stress in SSc-PAH in order to clarify the potential of XOR as a therapeutic target, and to lay a groundwork for personalized selection of PAH therapies in SSc.