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

项目总结/摘要 肺动脉高压是一种以肺血管重构和血气差为特征的疾病 交换，并最终导致右心室衰竭和死亡。心脏和呼吸肌升高 工作负荷有助于隔膜和心脏损害的PH;然而，生理和分子 基地还没有完全了解。PH时血管功能受损，导致无法匹配 氧气输送到需求，这在过度劳累的隔膜和心脏中越来越重要。 然而，PH诱导的血管功能障碍的潜在机制，以及更重要的靶点， 减轻这种功能障碍的方法仍然未知。活性氧和炎症反应的上调 细胞因子被认为促进PH发病，这表明细胞内氧化还原的调节 通路可能作为一种潜在的机制，负责受损的血管紧张素转换酶控制与PH， 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损害内皮依赖性和非依赖性血管舒张， 隔膜小动脉，因此动脉血流量。重要的是，内皮依赖性和- 非依赖性血管反应性可以通过激活转录因子，核因子红细胞样蛋白， 2-相关因子2（NRF 2）。然而，Nrf 2在改善冠状动脉和膈肌血管功能中的作用， PH值从未被确定。因此，我们的总体假设是，运动训练和 药理学Nrf 2激活将改善或恢复冠状动脉和膈肌血管功能， 博士此外，我们将评估这些适应对Nrf 2的依赖，以确定 可能的分子基础 该项目将在大卫博士的指导下在堪萨斯州立大学（KSU）完成。普尔 和布拉德利·J·本克。制定培训计划，以促进技术发展 执行拟议实验所需的专业和批判性思维技能，并结合 申请人过渡到独立的科学生涯所必需的要素。普尔和本克 KSU的运动机能学、解剖学和生理学系代表了丰富的 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 对健康和疾病患者膈肌血流调节和血管扩张控制机制的见解 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.