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oai:docta.ucm.es:20.500.14352/947382025-07-10T00:02:56Zcom_20.500.14352_14col_20.500.14352_15

Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction González Santamaría, José Villalba Orero, María Busnadiego, Oscar López Olañeta, Marina Sandoval, Pilar Snabel, Jessica López Cabrera, Manuel Erler, Janine T. Hanemaaijer, Roeland Lara Pezzi, Enrique Rodríguez Pascual, Fernando Aims: After myocardial infarction (MI), extensive remodelling of the extracellular matrix contributes to scar formation. While aiming to preserve tissue integrity, this fibrotic response is also associated with adverse events, including a markedly increased risk of heart failure, ventricular arrhythmias, and sudden cardiac death. Cardiac fibrosis is characterized by extensive deposition of collagen and also by increased stiffness as a consequence of enhanced collagen cross-linking. Members of the lysyl oxidase (LOX) family of enzymes are responsible for the formation of collagen cross-links. This study investigates the contribution of LOX family members to the heart response to MI. Methods and results: Experimental MI was induced in C57BL/6 mice by permanent ligation of the left anterior descending coronary artery. The expression of LOX isoforms (LOX and LOXL1-4) was strongly increased upon MI, and this response was accompanied by a significant accumulation of mature collagen fibres in the infarcted area. LOX expression was observed in areas of extensive remodelling, partially overlapping with α-smooth muscle actin-expressing myofibroblasts. Tumour growth factor-β as well as hypoxia-activated pathways contributed to the induction of LOX expression in cardiac fibroblasts. Finally, in vivo post-infarction treatment with the broadband LOX inhibitor β-aminopropionitrile or, selectively, with a neutralizing antibody against the canonical LOX isoform attenuated collagen accumulation and maturation and also resulted in reduced ventricular dilatation and improved cardiac function. Conclusion: LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery. 2024-01-23T12:21:48Z 2024-01-23T12:21:48Z 2024-01-23T12:21:48Z 2015 journal article https://hdl.handle.net/20.500.14352/94738 0008-6363 10.1093/cvr/cvv214 1755-3245 eng González-Santamaría J, Villalba M, Busnadiego O, López-Olañeta MM, Sandoval P, Snabel J, López-Cabrera M, Erler JT, Hanemaaijer R, Lara-Pezzi E, Rodríguez-Pascual F. Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction. Cardiovasc Res. 2016 Jan 1;109(1):67-78. doi: 10.1093/cvr/cvv214 restricted access Oxford University Press