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. Epub 2015 Aug 10.


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.

Keywords: Cardiac fibrosis; Collagen; Lysyl oxidases; Myocardial infarction; Myofibroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cells, Cultured
  • Enzyme Induction
  • Extracellular Matrix / physiology*
  • Heart / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / physiopathology
  • Protein-Lysine 6-Oxidase / antagonists & inhibitors
  • Protein-Lysine 6-Oxidase / biosynthesis*
  • Protein-Lysine 6-Oxidase / genetics
  • Transforming Growth Factor beta / pharmacology


  • Transforming Growth Factor beta
  • Protein-Lysine 6-Oxidase