title: Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome.
abstract: Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transforming growth factor-β (TGF-β)- and angiotensin II-dependent pathways, alterations in the vascular extracellular matrix (ECM) may also play a role in the onset and progression of the aortic disease. Lysyl oxidases (LOX) are extracellular enzymes, which initiates the formation of covalent cross-linking of collagens and elastin, thereby contributing to the maturation of the ECM. Here we have explored the role of LOX in the formation of aortic aneurysms in MFS. We show that aortic tissue from MFS patients and MFS mouse model (Fbn1(C1039G/+)) displayed enhanced expression of the members of the LOX family, LOX and LOX-like 1 (LOXL1), and this is associated with the formation of mature collagen fibers. Administration of a LOX inhibitor for 8weeks blocked collagen accumulation and aggravated elastic fiber impairment, and these effects correlated with the induction of a strong and rapidly progressing aortic dilatation, and with premature death in the more severe MFS mouse model, Fbn1(mgR/mgR), without any significant effect on wild type animals. This detrimental effect occurred preferentially in the ascending portion of the aorta, with little or no involvement of the aortic root, and was associated to an overactivation of both canonical and non-canonical TGF-β signaling pathways. The blockade of angiotensin II type I receptor with losartan restored TGF-β signaling activation, normalized elastic fiber impairment and prevented the aortic dilatation induced by LOX inhibition in Fbn1(C1039G/+) mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Busnadiego
authors.affiliation: Departamento de Biología Celular, Inmunología y Neurociencias, Facultad de Medicina, Universidad de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Gorbenko Del Blanco
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: González-Santamaría
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Habashi
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Calderon
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Fundación Banco Bilbao Vizcaya-CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Lopez-Cabrera
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Rosell-Garcia
authors.affiliation: TNO Metabolic Health Research, Leiden, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Snabel
authors.affiliation: TNO Metabolic Health Research, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Hanemaaijer
authors.affiliation: Hospital Universitario 12 de Octubre, Unidad de Marfan, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Forteza
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Departamento de Biología Celular, Inmunología y Neurociencias, Facultad de Medicina, Universidad de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Egea
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.)/Universidad Autónoma de Madrid (Madrid), Madrid, Spain. Electronic address: frodriguez@cbm.csic.es.
authors.forename: F
authors.initials: F
authors.lastname: Rodriguez-Pascual
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology; D001014:Aortic Aneurysm / Q000201:enzymology* / Q000209:etiology; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D008382:Marfan Syndrome / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*
chemical_list: D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human; D008249:Protein-Lysine 6-Oxidase
keywords: Aneurysm; Collagen; Extracellular matrix; Lysyl oxidases; Marfan syndrome; Transforming growth factor-β