Mitochondrial Dysfunction Underlies Right Ventricular Failure in Pulmonary Hypertension

 描述(申请人提供)：肺动脉高压(PH)是一种进行性肺血管疾病，导致右室(RV)衰竭。尽管有针对肺血管系统的药物可用，但在诊断为PH后，估计的中位存活率仍然低得令人无法接受。右室功能是PH患者发病率和死亡率的最重要决定因素。然而，PH时RV功能障碍的亚细胞机制尚不完全清楚。长时间的右室压力超负荷会导致组织重塑和最终的收缩功能衰竭。在实验和人体PH中，RV表现出糖酵解增加，提示代谢异常。在实验性PH中，RV产生的活性氧(ROS)似乎增加，这表明氧化信号和细胞损伤的机制错乱。线粒体对心肌细胞的功能至关重要，因为它们在能量代谢、细胞生存和增殖(细胞凋亡信号)和氧化剂信号转导中起着核心作用。然而，RV心肌细胞线粒体的缺陷还没有在人或实验性PH中得到全面的测量。此外，线粒体病理与RV的结构或血流动力学功能障碍之间的时间关系尚不清楚。我们在肺动脉环扎模型中的初步数据显示，在失代偿性RV衰竭开始之前，线粒体的早期变化(呼吸减少，生物发生信号增加，ROS增加)。我们推测，心肌细胞线粒体的形态和功能受损会导致压力超负荷性肺动脉高压时的右室衰竭。我们将通过对RV失代偿失代偿过程中线粒体功能的全面评估来检验这一假设。我们将结合器官和组织水平RV结构和功能的评估与线粒体呼吸、能量容量(ATP产生)、电子传递链酶活性和氧化剂产生的测量相结合。这项调查将为 开发线粒体靶向治疗肺高压RV衰竭策略的第一步。此外，了解线粒体功能障碍和RV生物力学变化的时间进程可以指导基于时间的策略来提供现有的治疗方法。这项NRSA将为候选人，一名肺部和重症监护医学研究员，提供一个机会来开发一种将线粒体生物学与肺血管疾病联系起来的研究图谱。导师团队Sruti Shiva博士(基础研究和线粒体生物学专家)、Mark Gladwin博士(肺科专家和PH专家)和Marc Simon(心脏病专家和生物力学专家)的经验，以及匹兹堡大学血管医学研究所(VMI)和心脏病学和肺医学系的资源将确保候选人成功接受培训。

 DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature which leads to right ventricular (RV) failure. Despite the availability of drugs targeting the pulmonary vasculature, estimated median survival after diagnosis of PH remains unacceptably low. RV function is the most important determinant of morbidity and mortality in patients with PH. However, the subcellular mechanisms underlying RV dysfunction in PH are not completely clear. Prolonged pressure overload on the RV leads to tissue remodeling and eventual contractile failure. The RV exhibits increased glycolysis in experimental and human PH, suggesting abnormal metabolism. Reactive oxygen species (ROS) generation by the RV in experimental PH appears to be increased, suggesting deranged oxidant signaling and a mechanism for cell damage. Mitochondria are vital to cardiac myocyte function owing to their central role in energy metabolism, cell survival and proliferation (apoptosis signaling), and oxidant signaling. However, defects in RV cardiac myocyte mitochondria have not been comprehensively measured in human or experimental PH. Furthermore, the chronological relationship between mitochondrial pathology and structural or hemodynamic dysfunction of the RV is not known. Our preliminary data in a pulmonary artery banding model of PH shows early mitochondrial changes (decreased respiration, increased biogenesis signaling, and increased ROS) prior to the onset of decompensated RV failure. We hypothesize that impaired cardiac myocyte mitochondrial morphology and function causes RV failure in pressure overload pulmonary hypertension. We will test this hypothesis by performing a comprehensive assessment of mitochondrial function over the time course of RV failure decompensation. We will combine the assessment of organ- and tissue-level RV structure and function with measurements of mitochondrial respiration, energetic capacity (ATP production), electron transport chain enzyme activity, and oxidant production. This investigation will offer the first steps to the development of mitochondrial targeted therapeutic strategies for the treatment of RV failure in PH. Moreover, understanding the time course of mitochondrial dysfunction and RV biomechanical changes could guide time-based strategies for delivering existing therapeutics. This NRSA will provide the candidate, a pulmonary and critical care medicine fellow, with an opportunity to develop a research repertoire bridging mitochondrial biology with pulmonary vascular disease. The experience of mentorship team Drs. Sruti Shiva (expert in basic research and mitochondrial biology), Mark Gladwin (pulmonologist and expert in PH), and Marc Simon (cardiologist and expert in biomechanics), and resources at the Vascular Medicine Institute (VMI) at the University of Pittsburgh and the Divisions of Cardiology and Pulmonary Medicine will ensure the candidate's successful training.