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

José González-Santamaría; María Villalba; Oscar Busnadiego; Marina M López-Olañeta; Pilar Sandoval; Jessica Snabel; Manuel López-Cabrera; Janine T Erler; Roeland Hanemaaijer; Enrique Lara-Pezzi; Fernando Rodríguez-Pascual

doi:10.1093/cvr/cvv214

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

José González-Santamaría, María Villalba, Oscar Busnadiego, Marina M López-Olañeta, Pilar Sandoval, Jessica Snabel, Manuel López-Cabrera, Janine T Erler, Roeland Hanemaaijer, Enrique Lara-Pezzi, Fernando Rodríguez-Pascual

63 Citations (Scopus)

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.

Original language	English
Journal	Cardiovascular Research
Volume	109
Issue number	1
Pages (from-to)	67-78
Number of pages	12
ISSN	0008-6363
DOIs	https://doi.org/10.1093/cvr/cvv214
Publication status	Published - 1 Jan 2016

Keywords

Journal Article
Research Support, Non-U.S. Gov't

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González-Santamaría, J., Villalba, M., Busnadiego, O., López-Olañeta, M. M., Sandoval, P., Snabel, J., López-Cabrera, M., Erler, J. T., Hanemaaijer, R., Lara-Pezzi, E., & Rodríguez-Pascual, F. (2016). Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction. Cardiovascular Research, 109(1), 67-78. https://doi.org/10.1093/cvr/cvv214

González-Santamaría, J, Villalba, M, Busnadiego, O, López-Olañeta, MM, Sandoval, P, Snabel, J, López-Cabrera, M, Erler, JT, Hanemaaijer, R, Lara-Pezzi, E & Rodríguez-Pascual, F 2016, 'Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction', Cardiovascular Research, vol. 109, no. 1, pp. 67-78. https://doi.org/10.1093/cvr/cvv214

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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.",

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T1 - Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction

AU - González-Santamaría, José

AU - Villalba, María

AU - Busnadiego, Oscar

AU - López-Olañeta, Marina M

AU - Sandoval, Pilar

AU - Snabel, Jessica

AU - López-Cabrera, Manuel

AU - Erler, Janine T

AU - Hanemaaijer, Roeland

AU - Lara-Pezzi, Enrique

AU - Rodríguez-Pascual, Fernando

PY - 2016/1/1

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N2 - 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.

AB - 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.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1093/cvr/cvv214

M3 - Journal article

C2 - 26260798

SN - 0008-6363

VL - 109

SP - 67

EP - 78

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -

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

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