HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension

Abstract Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a “cancer-like” pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmi...

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Autores principales:	Olivier Boucherat, Sophie Chabot, Roxane Paulin, Isabelle Trinh, Alice Bourgeois, François Potus, Marie-Claude Lampron, Caroline Lambert, Sandra Breuils-Bonnet, Valérie Nadeau, Renée Paradis, Elena A. Goncharova, Steeve Provencher, Sébastien Bonnet
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f90d5634c64f49ecb27fef8c14550b2f
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spelling	oai:doaj.org-article:f90d5634c64f49ecb27fef8c14550b2f2021-12-02T11:52:40ZHDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension10.1038/s41598-017-04874-42045-2322https://doaj.org/article/f90d5634c64f49ecb27fef8c14550b2f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04874-4https://doaj.org/toc/2045-2322Abstract Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a “cancer-like” pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. We found that HDAC6 is significantly up-regulated in lungs, distal PAs, and isolated PASMCs from PAH patients and animal models. Inhibition of HDAC6 reduced PAH-PASMC proliferation and resistance to apoptosis in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 maintains Ku70 in a hypoacetylated state, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo, pharmacological inhibition of HDAC6 improved established PAH in two experimental models and can be safely given in combination with currently approved PAH therapies. Moreover, Hdac6 deficient mice were partially protected against chronic hypoxia-induced pulmonary hypertension. Our study shows for the first time that HDAC6 is implicated in PAH development and represents a new promising target to improve PAH.Olivier BoucheratSophie ChabotRoxane PaulinIsabelle TrinhAlice BourgeoisFrançois PotusMarie-Claude LampronCaroline LambertSandra Breuils-BonnetValérie NadeauRenée ParadisElena A. GoncharovaSteeve ProvencherSébastien BonnetNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olivier Boucherat Sophie Chabot Roxane Paulin Isabelle Trinh Alice Bourgeois François Potus Marie-Claude Lampron Caroline Lambert Sandra Breuils-Bonnet Valérie Nadeau Renée Paradis Elena A. Goncharova Steeve Provencher Sébastien Bonnet HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
description	Abstract Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a “cancer-like” pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. We found that HDAC6 is significantly up-regulated in lungs, distal PAs, and isolated PASMCs from PAH patients and animal models. Inhibition of HDAC6 reduced PAH-PASMC proliferation and resistance to apoptosis in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 maintains Ku70 in a hypoacetylated state, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo, pharmacological inhibition of HDAC6 improved established PAH in two experimental models and can be safely given in combination with currently approved PAH therapies. Moreover, Hdac6 deficient mice were partially protected against chronic hypoxia-induced pulmonary hypertension. Our study shows for the first time that HDAC6 is implicated in PAH development and represents a new promising target to improve PAH.
format	article
author	Olivier Boucherat Sophie Chabot Roxane Paulin Isabelle Trinh Alice Bourgeois François Potus Marie-Claude Lampron Caroline Lambert Sandra Breuils-Bonnet Valérie Nadeau Renée Paradis Elena A. Goncharova Steeve Provencher Sébastien Bonnet
author_facet	Olivier Boucherat Sophie Chabot Roxane Paulin Isabelle Trinh Alice Bourgeois François Potus Marie-Claude Lampron Caroline Lambert Sandra Breuils-Bonnet Valérie Nadeau Renée Paradis Elena A. Goncharova Steeve Provencher Sébastien Bonnet
author_sort	Olivier Boucherat
title	HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
title_short	HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
title_full	HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
title_fullStr	HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
title_full_unstemmed	HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension
title_sort	hdac6: a novel histone deacetylase implicated in pulmonary arterial hypertension
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f90d5634c64f49ecb27fef8c14550b2f
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HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension

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