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Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome

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Author: Busnadiego, O. · Gorbenko del Blanco, D. · González-Santamaría, J. · Habashi, J.P. · Calderon, J.F. · Sandoval, P. · Bedja, D. · Guinea-Viniegra, J. · Lopez-Cabrera, M. · Rosell-Garcia, T. · Snabel, J.M. · Hanemaaijer, R. · Forteza, A. · Dietz, H.C. · Egea, G. · Rodriguez-Pascual, F.
Source:Journal of Molecular and Cellular Cardiology, 85, 48-57
Identifier: 526118
doi: doi:10.1016/j.yjmcc.2015.05.008
Keywords: Biology · Aneurysm · Collagen · Extracellular matrix · Lysyl oxidases · Marfan syndrome · Transforming growth factor-β · Losartan · Oxidoreductase · Protein LOXL1 · Protein lysine 6 oxidase · Transforming growth factor beta · Unclassified drug · Animal tissue · Aorta aneurysm · Clinical article · Collagen fiber · Controlled study · Disease association · Disease course · Disease severity · Elastic fiber · Enzyme inhibition · Human tissue · Marfan syndrome · Mouse · Mouse model · Nonhuman · Prophylaxis · Protein expression · Signal transduction · Upregulation · Wild type · Animalia · Mus · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences


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 (Fbn1C1039G/+) 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, Fbn1mgR/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 Fbn1C1039G/+ mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS. © 2015 Elsevier Ltd.