Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors

Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characteris...

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Authors: Galán, María, Varona, Saray, Orriols, Mar, Rodríguez, José Antonio, Aguiló, Silvia, Dilmé, Jaume, Camacho, Mercedes, Martínez-González, José, Tejedor-Rodríguez, Cristina
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/413819
Online Access:http://hdl.handle.net/10261/413819
https://api.elsevier.com/content/abstract/scopus_id/84966560292
Access Level:Open access
Keyword:Abdominal aortic aneurysm
Histone deacetylases
Inflammation
Metalloproteinases
Vascular remodelling
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spelling Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitorsGalán, MaríaVarona, SarayOrriols, MarRodríguez, José AntonioAguiló, SilviaDilmé, JaumeCamacho, MercedesMartínez-González, JoséTejedor-Rodríguez, CristinaAbdominal aortic aneurysmHistone deacetylasesInflammationMetalloproteinasesVascular remodellingClinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) [grants PI15/01016 and PI12/01952 to C.R.; SAF2012-40127 to J.M.-G.; SAF2013-46707-R to M.C., RD12/0042/0053 to J.M.-G. and C.R.; RD12/0042/0051 to MC and RD12/0042/0009 to J.A.R.]. The study was co-founded by Fondo Europeo de Desarrollo Regional (FEDER)-The way to build Europe. M.G. was supported by funds provided by ISCIII (Sara Borrell program).Peer reviewedCompany of BiologistsMinisterio de Economía y Competitividad (España)Instituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262016info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/413819https://api.elsevier.com/content/abstract/scopus_id/84966560292reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//PI15%2F01016info:eu-repo/grantAgreement/MINECO//PI12%2F01952info:eu-repo/grantAgreement/MINECO//SAF2012-40127info:eu-repo/grantAgreement/MINECO//SAF2013-46707-Rhttps://doi.org/10.1242/dmm.024513Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4138192026-05-22T06:33:51Z
dc.title.none.fl_str_mv Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
title Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
spellingShingle Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
Galán, María
Abdominal aortic aneurysm
Histone deacetylases
Inflammation
Metalloproteinases
Vascular remodelling
title_short Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
title_full Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
title_fullStr Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
title_full_unstemmed Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
title_sort Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
dc.creator.none.fl_str_mv Galán, María
Varona, Saray
Orriols, Mar
Rodríguez, José Antonio
Aguiló, Silvia
Dilmé, Jaume
Camacho, Mercedes
Martínez-González, José
Tejedor-Rodríguez, Cristina
author Galán, María
author_facet Galán, María
Varona, Saray
Orriols, Mar
Rodríguez, José Antonio
Aguiló, Silvia
Dilmé, Jaume
Camacho, Mercedes
Martínez-González, José
Tejedor-Rodríguez, Cristina
author_role author
author2 Varona, Saray
Orriols, Mar
Rodríguez, José Antonio
Aguiló, Silvia
Dilmé, Jaume
Camacho, Mercedes
Martínez-González, José
Tejedor-Rodríguez, Cristina
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Abdominal aortic aneurysm
Histone deacetylases
Inflammation
Metalloproteinases
Vascular remodelling
topic Abdominal aortic aneurysm
Histone deacetylases
Inflammation
Metalloproteinases
Vascular remodelling
description Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression.
publishDate 2016
dc.date.none.fl_str_mv 2016
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/413819
https://api.elsevier.com/content/abstract/scopus_id/84966560292
url http://hdl.handle.net/10261/413819
https://api.elsevier.com/content/abstract/scopus_id/84966560292
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//PI15%2F01016
info:eu-repo/grantAgreement/MINECO//PI12%2F01952
info:eu-repo/grantAgreement/MINECO//SAF2012-40127
info:eu-repo/grantAgreement/MINECO//SAF2013-46707-R
https://doi.org/10.1242/dmm.024513
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Company of Biologists
publisher.none.fl_str_mv Company of Biologists
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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