González-Santamaría, JoséVillalba, MaríaBusnadiego, OscarLopez-Olaneta, MarinaSandoval, PilarSnabel, JessicaLópez-Cabrera, ManuelErler, Janine THanemaaijer, RoelandLara-Pezzi, EnriqueRodríguez-Pascual, Fernando2019-07-292019-07-292016-01Cardiovasc Res. 2016; 109(1):67-780008-6363http://hdl.handle.net/20.500.12105/7985AIMS: 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.engAMhttp://creativecommons.org/licenses/by-nc-sa/4.0/Cardiac fibrosisCollagenLysyl oxidasesMyocardial infarctionMyofibroblastAnimalsCell HypoxiaCells, CulturedEnzyme InductionExtracellular MatrixHeartMiceMice, Inbred C57BLMyocardial InfarctionProtein-Lysine 6-OxidaseTransforming Growth Factor betaAtribución-NoComercial-CompartirIgual 4.0 Internacional26260798109167-7810.1093/cvr/cvv2141755-3245Cardiovascular researchopen access