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.

Public Health Relevance

Pulmonary hypertension leads to right ventricular failure which results in death. The subcellular mechanisms underlying right ventricular dysfunction in pulmonary hypertension are incompletely understood. Previous studies have shown derangements in cardiac cellular energy metabolism in human and experimental pulmonary hypertension. Mitochondria play a central role in cellular metabolism, particularly in cardiac muscle cells. We hypothesize that mitochondrial dysfunction underlies right ventricular failure in pulmonary hypertension. This grant proposes comprehensive investigation of mitochondrial function over the time course to right ventricular failure in a pulmonary artery banding animal model of pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Meadows, Tawanna
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Nguyen, Quyen L; Corey, Catherine; White, Pamela et al. (2017) Platelets from pulmonary hypertension patients show increased mitochondrial reserve capacity. JCI Insight 2:e91415