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Cardiovasc Res. 2016 Jan 1;109(1):67-78. doi: 10.1093/cvr/cvv214. Epub 2015 Aug 10.

Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction.

Author information

1
Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera 1, Madrid E28049, Spain.
2
Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid E28029, Spain.
3
TNO Metabolic Health Research, Leiden, The Netherlands.
4
Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, Denmark.
5
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.
6
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.

Abstract

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

PMID:
26260798
DOI:
10.1093/cvr/cvv214
[Indexed for MEDLINE]

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