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A role for fumarate hydratase in mediating oxidative effects of galectin-3 in human cardiac fibroblasts.
Int J Cardiol 2018; 258:217-223IJ

Abstract

AIMS

Galectin-3 (Gal-3), a β-galactoside-binding lectin involved in cardiac inflammation and fibrosis, could regulate oxidative stress, although the mechanisms have not been elucidated. We herein investigated the changes in oxidative stress-related mediators induced by Gal-3 in human cardiac fibroblasts and in pathological animal and human models of cardiac diseases.

RESULTS

Using quantitative proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated fumarate hydratase (FH) in human cardiac fibroblasts. In parallel, Gal-3 increased fumarate production in a time-dependent manner. Gal-3 treatment enhanced carbonylated proteins detected through OxyBlot technique. Interestingly, treatment of cells with fumarate induced oxidative stress, enhanced fibroblast activation markers and increased collagen and interleukin-6 secretion. In Gal-3-silenced cells and in heart from Gal-3 knock-out mice, FH was increased and fumarate was decreased. In myocardial biopsies from patients with aortic stenosis (AS, n=26), FH levels were decreased as compared to Controls (n=13). Cardiac Gal-3 inversely correlated with FH levels in myocardial biopsies. In an experimental model of AS rats, pharmacological inhibition of Gal-3 restored cardiac FH, decreased fumarate concentration and improved oxidative status.

CONCLUSION

In human cardiac fibroblasts, Gal-3 decreased FH expression increasing fumarate concentration and promoting oxidative stress. In human AS, cardiac levels of Gal-3 inversely associated with FH. Gal-3 blockade restored FH and improved fumarate and oxidative stress status in AS rats. FH is therefore a key molecule mediating Gal-3-induced oxidative stress in cardiac cells.

Authors+Show Affiliations

Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.Department 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.INSERM, 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.INSERM, 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.Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; INSERM, 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. Electronic address: natalia.lopez.andres@navarra.es.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29544935

Citation

Ibarrola, Jaime, et al. "A Role for Fumarate Hydratase in Mediating Oxidative Effects of Galectin-3 in Human Cardiac Fibroblasts." International Journal of Cardiology, vol. 258, 2018, pp. 217-223.
Ibarrola J, Sádaba R, Garcia-Peña A, et al. A role for fumarate hydratase in mediating oxidative effects of galectin-3 in human cardiac fibroblasts. Int J Cardiol. 2018;258:217-223.
Ibarrola, J., Sádaba, R., Garcia-Peña, A., Arrieta, V., Martinez-Martinez, E., Alvarez, V., ... López-Andrés, N. (2018). A role for fumarate hydratase in mediating oxidative effects of galectin-3 in human cardiac fibroblasts. International Journal of Cardiology, 258, pp. 217-223. doi:10.1016/j.ijcard.2017.12.103.
Ibarrola J, et al. A Role for Fumarate Hydratase in Mediating Oxidative Effects of Galectin-3 in Human Cardiac Fibroblasts. Int J Cardiol. 2018 05 1;258:217-223. PubMed PMID: 29544935.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A role for fumarate hydratase in mediating oxidative effects of galectin-3 in human cardiac fibroblasts. AU - Ibarrola,Jaime, AU - Sádaba,Rafael, AU - Garcia-Peña,Amaia, AU - Arrieta,Vanessa, AU - Martinez-Martinez,Ernesto, AU - Alvarez,Virginia, AU - Fernández-Celis,Amaya, AU - Gainza,Alicia, AU - Santamaría,Enrique, AU - Fernández-Irigoyen,Joaquin, AU - Cachofeiro,Victoria, AU - Fay,Renaud, AU - Rossignol,Patrick, AU - López-Andrés,Natalia, PY - 2017/10/24/received PY - 2017/12/15/revised PY - 2017/12/28/accepted PY - 2018/3/17/entrez PY - 2018/3/17/pubmed PY - 2018/10/26/medline KW - Aortic stenosis KW - Fibroblasts KW - Fumarate hydratase KW - Galectin-3 SP - 217 EP - 223 JF - International journal of cardiology JO - Int. J. Cardiol. VL - 258 N2 - AIMS: Galectin-3 (Gal-3), a β-galactoside-binding lectin involved in cardiac inflammation and fibrosis, could regulate oxidative stress, although the mechanisms have not been elucidated. We herein investigated the changes in oxidative stress-related mediators induced by Gal-3 in human cardiac fibroblasts and in pathological animal and human models of cardiac diseases. RESULTS: Using quantitative proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated fumarate hydratase (FH) in human cardiac fibroblasts. In parallel, Gal-3 increased fumarate production in a time-dependent manner. Gal-3 treatment enhanced carbonylated proteins detected through OxyBlot technique. Interestingly, treatment of cells with fumarate induced oxidative stress, enhanced fibroblast activation markers and increased collagen and interleukin-6 secretion. In Gal-3-silenced cells and in heart from Gal-3 knock-out mice, FH was increased and fumarate was decreased. In myocardial biopsies from patients with aortic stenosis (AS, n=26), FH levels were decreased as compared to Controls (n=13). Cardiac Gal-3 inversely correlated with FH levels in myocardial biopsies. In an experimental model of AS rats, pharmacological inhibition of Gal-3 restored cardiac FH, decreased fumarate concentration and improved oxidative status. CONCLUSION: In human cardiac fibroblasts, Gal-3 decreased FH expression increasing fumarate concentration and promoting oxidative stress. In human AS, cardiac levels of Gal-3 inversely associated with FH. Gal-3 blockade restored FH and improved fumarate and oxidative stress status in AS rats. FH is therefore a key molecule mediating Gal-3-induced oxidative stress in cardiac cells. SN - 1874-1754 UR - https://www.unboundmedicine.com/medline/citation/29544935/A_role_for_fumarate_hydratase_in_mediating_oxidative_effects_of_galectin_3_in_human_cardiac_fibroblasts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-5273(17)36609-3 DB - PRIME DP - Unbound Medicine ER -