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

点击翻译按钮获取中文摘要

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.