%0 Journal Article
%A González Santamaría, José
%A Villalba Orero, María
%A Busnadiego, Oscar
%A López Olañeta, Marina
%A Sandoval, Pilar
%A Snabel, Jessica
%A López Cabrera, Manuel
%A Erler, Janine T.
%A Hanemaaijer, Roeland
%A Lara Pezzi, Enrique
%A Rodríguez Pascual, Fernando
%T Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction
%D 2015
%@ 0008-6363
%@ 1755-3245
%U https://hdl.handle.net/20.500.14352/94738
%X 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.
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