Indexado en

Licencia y uso

Citaciones

Cited 78 times in

Cited 64 times in

Cited 44 times in

Cited 68 times in

Altmetrics

Grant support

This study was supported by the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), the European Regional Development Fund, and the European Commission through H2020-EU.1.1, European Research Council grant ERC-2016-StG 715322-EndoMitTalk, and Gobierno de Espana SAF2016-80305P. This work was partially supported by Comunidad de Madrid (S2017/BMD 3867 RENIM-CM) and cofinanced by the European Structural and Investment Fund. M.M. is supported by the Miguel Servet Program (CP 19/014, Fundacion de Investigacion del Hospital 12 de Octubre). J.O., E.G., and R.R-D. are supported by Juan de la Cierva (FJCI2017-33855, IJC2018-036850-I, and IJCI-2017-31399, respectively). Support was also provided by Ministerio de Ciencia e Innovacion grants (RTI2018-099246-B-I00 to J.M.R. and PI18/00543 to J.F.N.) and Comunidad de Madrid and Fondo Social Europeo funds (AORTASANA-CM; B2017/BMD-3676 to A.M.B., A.F., and J.M.R.). J.M.R. was also funded by Fundacion La Caixa (HR18-00068) and the Marfan Foundation (USA). J.M.R. and J.L.M.V. were also funded by Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares of Ministerio de Ciencia e Innovacion (CB16/11/00264). J.F.N. was funded by Ministerio de Economia y Competitividad (PI18/00543) and Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares (CB16/11/00264), and was cofunded by Fondo Europeo de Desarrollo Regional.

Análisis de autorías institucional

Compartir

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Publicado en:CIRCULATION. 143 (21): 2091-2109 - 2021-05-25 143(21), DOI: 10.1161/CIRCULATIONAHA.120.051171

Autores: Oller, Jorge; Gabande-Rodriguez, Enrique; Ruiz-Rodriguez, Maria Jesus; Desdin-Mico, Gabriela; Aranda, Juan Francisco; Rodrigues-Diez, Raquel; Ballesteros-Martinez, Constanza; Blanco, Eva Maria; Roldan-Montero, Raquel; Acuna, Pedro; Nistal, J Francisco; Lino Cardenas, Christian L; Lindsay, Mark Evan; Martin-Ventura, Jose Luis; Briones, Ana M; Miguel Redondo, Juan; Mittelbrunn, Maria

Afiliaciones

Resumen

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 (Fbn1(c1039g/+)) 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-Cre(ERT2)Tfam(flox/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 Fbn1(c1039g/+) 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 Fbn1(c1039g/+) 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 Fbn1(c1039g/+) 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.

Palabras clave