title: Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice.
abstract: Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH.
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Rachel P
authors: RP
authors: Heilman
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Megan B
authors: MB
authors: Lagoski
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Keng Jin
authors: KJ
authors: Lee
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Joann M
authors: JM
authors: Taylor
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Gina A
authors: GA
authors: Kim
authors: Pediatrics, Northwestern University, Chicago, Illinois; and.
authors: Sara K
authors: SK
authors: Berkelhamer
authors: Pediatrics, University of California, Davis, California.
authors: Robin H
authors: RH
authors: Steinhorn
authors: Pediatrics, Northwestern University, Chicago, Illinois; and k-farrow@northwestern.edu.
authors: Kathryn N
authors: http://orcid.org/0000-0002-8604-7023
authors: KN
authors: Farrow
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D018496:Hyperoxia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse
keywords: PDE5; cyclic nucleotides; pulmonary hypertension; right ventricle