Role for Nrf2 and exercise in mitigating pulmonary hypertension-induced vascular dysfunction

项目摘要/摘要 肺动脉高压(PH)是一种以肺血管重构和气体贫乏为特征的疾病。 交换，并最终导致右心衰竭和死亡。心脏和呼吸肌升高 工作负荷会导致PH患者的隔膜和心脏损害；然而，生理和分子方面的 碱基还没有完全被理解。PH患者的血管功能受损，导致无法匹配 氧气输送到需求，这在过度劳累的横隔膜和心脏中变得越来越重要。 然而，PH诱导血管功能障碍的潜在机制，以及更重要的靶点， 缓解这种功能障碍的方法尚不清楚。活性氧自由基的上调与炎症 细胞因子被认为促进了PH的发病，这表明细胞内氧化还原的调节 通路可能是导致肺高压患者血管运动控制受损的潜在机制之一。 为改善PH患者受损的血管功能提供了潜在的治疗靶点。 初步数据支持PH损害血管内皮细胞依赖性和非依赖性血管松弛 横隔膜小动脉，因此横隔膜的血液流动。重要的是，内皮依赖和- 独立的血管反应性可通过激活转录因子、核因子红系- 2相关因子2(Nrf2)。然而，Nrf2在改善冠状动脉和横隔膜血管功能方面的作用 PH值一直没有确定下来。因此，我们的全球假设是运动训练和 药物激活Nrf2将改善或恢复冠脉和横隔膜血管功能 pH值此外，我们将评估这些适应对NRF2的依赖程度，以确定 为我们的发现提供潜在的分子基础。 这个项目将在堪萨斯州立大学(KSU)完成，由David C.Poole博士指导 和布拉德利·J·本克。制定了培训计划，以促进技术的发展 执行拟议实验所需的熟练程度和批判性思维技能，并结合 申请人过渡到独立的科学事业所必需的要素。普尔和本克 实验室，以及KSU的运动学、解剖学和生理学系代表着丰富的 科学环境，将提供优秀的研究生培训和研究机会，以获得新的 健康人和疾病人膈肌血流调节和血管运动控制机制的研究 动物模型。

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a disease characterized by pulmonary vascular remodeling and poor gas exchange, and eventually leads to right ventricular failure and death. Elevated heart and respiratory muscle workloads contribute to diaphragm and cardiac impairments in PH; however, the physiological and molecular bases are not fully understood. Vascular function is compromised in PH, resulting in an inability to match oxygen delivery to demand, which is of increasing importance in the overworked diaphragm and heart. However, the mechanisms underlying PH-induced vascular dysfunction and, arguably more important, targets for mitigating such dysfunction remain unknown. Upregulation of reactive oxygen species and inflammatory cytokines are thought to promote PH pathogenesis, which suggests that modulation of intracellular redox pathways may serve as one potential mechanism responsible for the impaired vasomotor control with PH and provides a potential therapeutic target to improve the compromised vascular function in PH. Preliminary data supports that PH impairs endothelial-dependent and -independent vasorelaxation in diaphragm arterioles, and therefore diaphragmatic blood flow. Importantly, endothelial-dependent and - independent vasoreactivity may be improved by activation of the transcription factor, nuclear factor erythroid- 2–related factor 2 (Nrf2). However, the role of Nrf2 in improving coronary and diaphragm vascular function in PH has never been determined. Therefore, our global hypothesis is that exercise training and pharmacological Nrf2 activation will improve or restore coronary and diaphragm vascular function in PH. Furthermore, we will assess the reliance upon Nrf2 for these adaptations in order to determine the potential molecular basis for our findings. This project will be completed at Kansas State University (KSU) under the guidance of Drs. David C. Poole and Bradley J. Behnke. The training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the elements essential for the applicant to transition into an independent scientific career. The Poole and Behnke Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich scientific environment that will provide outstanding graduate training and research opportunities to gain new insights into mechanisms of diaphragm blood flow regulation and vasomotor control in healthy and diseased animal models.