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Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension

Pulmonary hypertension (PH) is an incurable condition in humans; driven by pulmonary vascular remodeling partially mediated by epigenetic mechanisms; and leading to right ventricular hypertrophy, failure, and death. We hypothesized that targeting chromatin-modifying histone deacetylases may provide...

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Autores principales: Applegate, Tanya J., Krafsur, Greta M., Boon, June A., Zhang, Hui, Li, Min, Holt, Timothy N., Ambler, S. Kelly, Abrams, Benjamin A., Gustafson, Daniel L., Bartels, Karsten, Garry, Franklyn B., Stenmark, Kurt R., Brown, R. Dale
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450341/
https://www.ncbi.nlm.nih.gov/pubmed/34552503
http://dx.doi.org/10.3389/fphys.2021.712583
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author Applegate, Tanya J.
Krafsur, Greta M.
Boon, June A.
Zhang, Hui
Li, Min
Holt, Timothy N.
Ambler, S. Kelly
Abrams, Benjamin A.
Gustafson, Daniel L.
Bartels, Karsten
Garry, Franklyn B.
Stenmark, Kurt R.
Brown, R. Dale
author_facet Applegate, Tanya J.
Krafsur, Greta M.
Boon, June A.
Zhang, Hui
Li, Min
Holt, Timothy N.
Ambler, S. Kelly
Abrams, Benjamin A.
Gustafson, Daniel L.
Bartels, Karsten
Garry, Franklyn B.
Stenmark, Kurt R.
Brown, R. Dale
author_sort Applegate, Tanya J.
collection PubMed
description Pulmonary hypertension (PH) is an incurable condition in humans; driven by pulmonary vascular remodeling partially mediated by epigenetic mechanisms; and leading to right ventricular hypertrophy, failure, and death. We hypothesized that targeting chromatin-modifying histone deacetylases may provide benefit. In this Brief Report we describe case comparison studies using the histone deacetylase inhibitor vorinostat (suberanilohydroxamic acid, 5 mg/kg/day for the first 5 study days) in an established model of severe neonatal bovine PH induced by 14 days of environmental hypoxia. Echocardiographic, hemodynamic, and pharmacokinetic data were obtained in hypoxia-exposed (one each, vorinostat-treated vs. untreated) and normoxic vorinostat-treated control animals (n = 2). Echocardiography detected PH changes by day 4 and severe PH over 14 days of continued hypoxic exposure. RV dysfunction at day 4 was less severe in vorinostat-treated compared to untreated hypoxic calves. Cardioprotective effects were partially maintained following cessation of treatment through the duration of hypoxic exposure, accompanied by hemodynamic evidence suggestive of reduced pulmonary vascular stiffening, and modulated expression of HDAC1 protein and genes involved in RV and pulmonary vascular remodeling and pathological RV hypertrophy. Control calves did not develop PH, nor show adverse cardiac or clinical effects. These results provide novel translation of epigenetic-directed therapy to a large animal severe PH model that recapitulates important features of human disease.
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spelling pubmed-84503412021-09-21 Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension Applegate, Tanya J. Krafsur, Greta M. Boon, June A. Zhang, Hui Li, Min Holt, Timothy N. Ambler, S. Kelly Abrams, Benjamin A. Gustafson, Daniel L. Bartels, Karsten Garry, Franklyn B. Stenmark, Kurt R. Brown, R. Dale Front Physiol Physiology Pulmonary hypertension (PH) is an incurable condition in humans; driven by pulmonary vascular remodeling partially mediated by epigenetic mechanisms; and leading to right ventricular hypertrophy, failure, and death. We hypothesized that targeting chromatin-modifying histone deacetylases may provide benefit. In this Brief Report we describe case comparison studies using the histone deacetylase inhibitor vorinostat (suberanilohydroxamic acid, 5 mg/kg/day for the first 5 study days) in an established model of severe neonatal bovine PH induced by 14 days of environmental hypoxia. Echocardiographic, hemodynamic, and pharmacokinetic data were obtained in hypoxia-exposed (one each, vorinostat-treated vs. untreated) and normoxic vorinostat-treated control animals (n = 2). Echocardiography detected PH changes by day 4 and severe PH over 14 days of continued hypoxic exposure. RV dysfunction at day 4 was less severe in vorinostat-treated compared to untreated hypoxic calves. Cardioprotective effects were partially maintained following cessation of treatment through the duration of hypoxic exposure, accompanied by hemodynamic evidence suggestive of reduced pulmonary vascular stiffening, and modulated expression of HDAC1 protein and genes involved in RV and pulmonary vascular remodeling and pathological RV hypertrophy. Control calves did not develop PH, nor show adverse cardiac or clinical effects. These results provide novel translation of epigenetic-directed therapy to a large animal severe PH model that recapitulates important features of human disease. Frontiers Media S.A. 2021-09-06 /pmc/articles/PMC8450341/ /pubmed/34552503 http://dx.doi.org/10.3389/fphys.2021.712583 Text en Copyright © 2021 Applegate, Krafsur, Boon, Zhang, Li, Holt, Ambler, Abrams, Gustafson, Bartels, Garry, Stenmark and Brown. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Applegate, Tanya J.
Krafsur, Greta M.
Boon, June A.
Zhang, Hui
Li, Min
Holt, Timothy N.
Ambler, S. Kelly
Abrams, Benjamin A.
Gustafson, Daniel L.
Bartels, Karsten
Garry, Franklyn B.
Stenmark, Kurt R.
Brown, R. Dale
Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title_full Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title_fullStr Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title_full_unstemmed Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title_short Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
title_sort brief report: case comparison of therapy with the histone deacetylase inhibitor vorinostat in a neonatal calf model of pulmonary hypertension
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450341/
https://www.ncbi.nlm.nih.gov/pubmed/34552503
http://dx.doi.org/10.3389/fphys.2021.712583
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