title: Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery.
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain.
authors.forename: José
authors.initials: J
authors.lastname: González-Santamaría
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid E28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Villalba
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Busnadiego
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid E28029, Spain.
authors.forename: Marina M
authors.initials: MM
authors.lastname: López-Olañeta
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: TNO Metabolic Health Research, Leiden, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Snabel
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, Denmark.
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
authors.affiliation: TNO Metabolic Health Research, Leiden, The Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Hanemaaijer
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid E28029, Spain frodriguez@cbm.csic.es elara@cnic.es.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain frodriguez@cbm.csic.es elara@cnic.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Pascual
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016212:Transforming Growth Factor beta; D008249:Protein-Lysine 6-Oxidase
keywords: Cardiac fibrosis; Collagen; Lysyl oxidases; Myocardial infarction; Myofibroblast