Galectin-3 (Gal-3) is increased in heart failure (HF) and promotes cardiac fibrosis and inflammation. We investigated whether Gal-3 modulates oxidative stress in human cardiac fibroblasts, in experimental animal models and in human aortic stenosis (AS). Using proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. In parallel, Gal-3 increased peroxide, nitrotyrosine, malondialdehyde, and N-carboxymethyl-lysine levels and decreased total antioxidant capacity. Gal-3 decreased prohibitin-2 expression without modifying other mitochondrial proteins. Prx-4 silencing increased oxidative stress markers. In Gal-3-silenced cells and in heart from Gal-3 knockout mice, Prx-4 was increased and oxidative stress markers were decreased. Pharmacological inhibition of Gal-3 with modified citrus pectin restored cardiac Prx-4 as well as prohibitin-2 levels and improved oxidative status in spontaneously hypertensive rats. In serum from 87 patients with AS, Gal-3 negatively correlated with total antioxidant capacity and positively correlated with peroxide. In myocardial biopsies from 26 AS patients, Gal-3 up-regulation paralleled a decrease in Prx-4 and in prohibitin-2. Cardiac Gal-3 inversely correlated with Prx-4 levels in myocardial biopsies. These data suggest that Gal-3 decreased Prx-4 antioxidant system in cardiac fibroblasts, increasing oxidative stress. In pathological models presenting enhanced cardiac Gal-3, the decrease in Prx-4 expression paralleled increased oxidative stress. Gal-3 blockade restored Prx-4 expression and improved oxidative stress status. In AS, circulating levels of Gal-3 could reflect oxidative stress. The alteration of the balance between antioxidant systems and reactive oxygen species production could be a new pathogenic mechanism by which Gal-3 induces cardiac damage in HF.
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July 2018
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The 3D structure of recombinant human deoxyribonuclease I. The N-terminal leucine shown in yellow at the top of the structure was selected for PEGylation of the protein. The amino acids shown in yellow towards the bottom of the protein are those interacting with globular actin, a potent inhibitor of human deoxyribonuclease I; for details, see pages 1439–1452.
Research Article|
July 18 2018
Galectin-3 down-regulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: a new pathway to induce cardiac damage
Jaime Ibarrola;
Jaime Ibarrola
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Vanessa Arrieta;
Vanessa Arrieta
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Rafael Sádaba;
Rafael Sádaba
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Ernesto Martinez-Martinez;
Ernesto Martinez-Martinez
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Amaia Garcia-Peña;
Amaia Garcia-Peña
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Virginia Alvarez;
Virginia Alvarez
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Amaya Fernández-Celis;
Amaya Fernández-Celis
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Alicia Gainza;
Alicia Gainza
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Enrique Santamaría;
Enrique Santamaría
2Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Joaquin Fernández-Irigoyen;
Joaquin Fernández-Irigoyen
2Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
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Victoria Cachofeiro;
Victoria Cachofeiro
3Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciber de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
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Guillermo Zalba;
Guillermo Zalba
4Department of Biochemistry and Genetics, University of Navarra, IdiSNA, Pamplona, Spain
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Renaud Fay;
Renaud Fay
5INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France
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Patrick Rossignol;
Patrick Rossignol
5INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France
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Natalia López-Andrés
1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
5INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France
Correspondence: Natalia López-Andrés (natalia.lopez.andres@navarra.es)
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Publisher: Portland Press Ltd
Received:
September 27 2017
Revision Received:
April 10 2018
Accepted:
April 18 2018
Accepted Manuscript online:
April 19 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (13): 1471–1485.
Article history
Received:
September 27 2017
Revision Received:
April 10 2018
Accepted:
April 18 2018
Accepted Manuscript online:
April 19 2018
Connected Content
A commentary has been published:
Protective role of peroxiredoxin-4 in heart failure
See also
Citation
Jaime Ibarrola, Vanessa Arrieta, Rafael Sádaba, Ernesto Martinez-Martinez, Amaia Garcia-Peña, Virginia Alvarez, Amaya Fernández-Celis, Alicia Gainza, Enrique Santamaría, Joaquin Fernández-Irigoyen, Victoria Cachofeiro, Guillermo Zalba, Renaud Fay, Patrick Rossignol, Natalia López-Andrés; Galectin-3 down-regulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: a new pathway to induce cardiac damage. Clin Sci (Lond) 18 July 2018; 132 (13): 1471–1485. doi: https://doi.org/10.1042/CS20171389
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