Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784569621396848640 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8450341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT applegatetanyaj briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT krafsurgretam briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT boonjunea briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT zhanghui briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT limin briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT holttimothyn briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT amblerskelly briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT abramsbenjamina briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT gustafsondaniell briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT bartelskarsten briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT garryfranklynb briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT stenmarkkurtr briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension AT brownrdale briefreportcasecomparisonoftherapywiththehistonedeacetylaseinhibitorvorinostatinaneonatalcalfmodelofpulmonaryhypertension |