A role for fumarate hydratase in mediating oxidative effects of galectin-3 in human cardiac fibroblasts. (1st May 2018)

• Record Type: Journal Article
• Authors: Ibarrola, Jaime; Sádaba, Rafael; Garcia-Peña, Amaia; Arrieta, Vanessa; Martinez-Martinez, Ernesto; Alvarez, Virginia; Fernández-Celis, Amaya; Gainza, Alicia; Santamaría, Enrique; Fernández-Irigoyen, Joaquin; Cachofeiro, Victoria; Fay, Renaud; Rossignol, Patrick; López-Andrés, Natalia
• Is Part Of: International journal of cardiology. Volume 258(2018)
• Page Start: 217
• Page End: 223
• Publication Date: 2018-05-01
• Subjects: Galectin-3 -- Fumarate hydratase -- Fibroblasts -- Aortic stenosis; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2017.12.103
• Languages: English
• ISSNs: 0167-5273

Abstract

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