Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thor...

ver descrição completa

Detalhes bibliográficos
Autores: Oller, Jorge, Gabandé-Rodriguez, Enrique, Ruiz-Rodríguez, Maria Jesús, Desdín-Micó, Gabriela, Aranda Gómez, Juan Francisco, Ballesteros-Rodríguez, Constanza, Blanco, Eva Maria, Roldán-Montero, Raquel, Acuña, Pedro, Forteza-Gil, Alberto, Martín-López, Carlos, Nistal, Francisco, Lino Cardenas, Christian, Evan, Lindsay, Martín-Vertura, Jose Luis, Briones, Ana, Redondo, Juan Miguel, Mittelbrunn, María
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/94925
Acesso em linha:https://hdl.handle.net/20.500.14352/94925
Access Level:acceso abierto
Palavra-chave:576.311.317
Aortic aneurysm
DNA
Mitochondrial
Extracellular matrix
Genetic diseases
Inborn
Glycolysis
Marfan syndrome
Muscle
Smooth
Vascular
Biología celular (Biología)
Cardiología
2407 Biología Celular
id ES_f33eea4c3b2602bbf13eef131ad80e30
oai_identifier_str oai:docta.ucm.es:20.500.14352/94925
network_acronym_str ES
network_name_str España
repository_id_str
spelling Extracellular Tuning of Mitochondrial Respiration Leads to Aortic AneurysmOller, JorgeGabandé-Rodriguez, EnriqueRuiz-Rodríguez, Maria JesúsDesdín-Micó, GabrielaAranda Gómez, Juan FranciscoBallesteros-Rodríguez, ConstanzaBlanco, Eva MariaRoldán-Montero, RaquelAcuña, PedroForteza-Gil, AlbertoMartín-López, CarlosNistal, FranciscoLino Cardenas, ChristianEvan, LindsayMartín-Vertura, Jose LuisBriones, AnaRedondo, Juan MiguelMittelbrunn, María576.311.317Aortic aneurysmDNAMitochondrialExtracellular matrixGenetic diseasesInbornGlycolysisMarfan syndromeMuscleSmoothVascularBiología celular (Biología)Cardiología2407 Biología CelularBackground: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.Universidad Complutense de Madrid20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/94925reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengEC PF7 Not available 715322open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/949252026-06-02T12:44:21Z
dc.title.none.fl_str_mv Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
title Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
spellingShingle Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
Oller, Jorge
576.311.317
Aortic aneurysm
DNA
Mitochondrial
Extracellular matrix
Genetic diseases
Inborn
Glycolysis
Marfan syndrome
Muscle
Smooth
Vascular
Biología celular (Biología)
Cardiología
2407 Biología Celular
title_short Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
title_full Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
title_fullStr Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
title_full_unstemmed Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
title_sort Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
dc.creator.none.fl_str_mv Oller, Jorge
Gabandé-Rodriguez, Enrique
Ruiz-Rodríguez, Maria Jesús
Desdín-Micó, Gabriela
Aranda Gómez, Juan Francisco
Ballesteros-Rodríguez, Constanza
Blanco, Eva Maria
Roldán-Montero, Raquel
Acuña, Pedro
Forteza-Gil, Alberto
Martín-López, Carlos
Nistal, Francisco
Lino Cardenas, Christian
Evan, Lindsay
Martín-Vertura, Jose Luis
Briones, Ana
Redondo, Juan Miguel
Mittelbrunn, María
author Oller, Jorge
author_facet Oller, Jorge
Gabandé-Rodriguez, Enrique
Ruiz-Rodríguez, Maria Jesús
Desdín-Micó, Gabriela
Aranda Gómez, Juan Francisco
Ballesteros-Rodríguez, Constanza
Blanco, Eva Maria
Roldán-Montero, Raquel
Acuña, Pedro
Forteza-Gil, Alberto
Martín-López, Carlos
Nistal, Francisco
Lino Cardenas, Christian
Evan, Lindsay
Martín-Vertura, Jose Luis
Briones, Ana
Redondo, Juan Miguel
Mittelbrunn, María
author_role author
author2 Gabandé-Rodriguez, Enrique
Ruiz-Rodríguez, Maria Jesús
Desdín-Micó, Gabriela
Aranda Gómez, Juan Francisco
Ballesteros-Rodríguez, Constanza
Blanco, Eva Maria
Roldán-Montero, Raquel
Acuña, Pedro
Forteza-Gil, Alberto
Martín-López, Carlos
Nistal, Francisco
Lino Cardenas, Christian
Evan, Lindsay
Martín-Vertura, Jose Luis
Briones, Ana
Redondo, Juan Miguel
Mittelbrunn, María
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 576.311.317
Aortic aneurysm
DNA
Mitochondrial
Extracellular matrix
Genetic diseases
Inborn
Glycolysis
Marfan syndrome
Muscle
Smooth
Vascular
Biología celular (Biología)
Cardiología
2407 Biología Celular
topic 576.311.317
Aortic aneurysm
DNA
Mitochondrial
Extracellular matrix
Genetic diseases
Inborn
Glycolysis
Marfan syndrome
Muscle
Smooth
Vascular
Biología celular (Biología)
Cardiología
2407 Biología Celular
description Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/94925
url https://hdl.handle.net/20.500.14352/94925
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv EC PF7 Not available 715322
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424359424131072
score 15,300719

Registos relacionados