title: Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis.
abstract: Prematurity complicates 12% of births, and young adults with a history of prematurity are at risk to develop right ventricular (RV) hypertrophy and impairment. The long-term risk for pulmonary vascular disease, as well as mechanisms of RV dysfunction and ventricular-vascular uncoupling after prematurity, remain poorly defined. Using an established model of prematurity-related lung disease, pups from timed-pregnant Sprague Dawley rats were randomized to normoxia or hyperoxia (fraction of inspired oxygen, 0.85) exposure for the first 14 days of life. After aging to 1 year in standard conditions, rats underwent hemodynamic assessment followed by tissue harvest for biochemical and histological evaluation. Aged hyperoxia-exposed rats developed significantly greater RV hypertrophy, associated with a 40% increase in RV systolic pressures. Although cardiac index was similar, hyperoxia-exposed rats demonstrated a reduced RV ejection fraction and significant RV-pulmonary vascular uncoupling. Hyperoxia-exposed RV cardiomyocytes demonstrated evidence of mitochondrial dysregulation and mitochondrial DNA damage, suggesting potential mitochondrial dysfunction as a cause of RV dysfunction. Aged rats exposed to postnatal hyperoxia recapitulate many features of young adults born prematurely, including increased RV hypertrophy and decreased RV ejection fraction. Our data suggest that postnatal hyperoxia exposure results in mitochondrial dysregulation that persists into adulthood with eventual RV dysfunction. Further evaluation of long-term mitochondrial function is warranted in both animal models of premature lung disease and in human adults who were born preterm.
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Kara N
authors.initials: KN
authors.lastname: Goss
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumari
authors.affiliation: 3 Division of Pediatric Critical Care, Department of Pediatrics.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tetri
authors.affiliation: 3 Division of Pediatric Critical Care, Department of Pediatrics.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Greg
authors.initials: G
authors.lastname: Barton
authors.affiliation: 3 Division of Pediatric Critical Care, Department of Pediatrics.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Rudolf K
authors.initials: RK
authors.lastname: Braun
authors.affiliation: 4 Cardiovascular Research Center, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: 3 Division of Pediatric Critical Care, Department of Pediatrics.|2 Rankin Laboratory of Pulmonary Medicine, and.
authors.forename: Marlowe W
authors.initials: MW
authors.lastname: Eldridge
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D001835:Body Weight; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D006439:Hemodynamics; D018496:Hyperoxia / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D001678:Organelle Biogenesis; D017207:Rats, Sprague-Dawley; D016278:Ventricular Function, Right
chemical_list: D004272:DNA, Mitochondrial
keywords: mitochondrial biogenesis; prematurity; pulmonary hypertension