Galectin-3 down-regulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: a new pathway to induce cardiac damage

Clin Sci (Lond). 2018 Jul 18;132(13):1471-1485. doi: 10.1042/CS20171389. Print 2018 Jul 18.

Abstract

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.

Keywords: antioxidant response elements; cardiac fibroblasts; galectins; peroxiredoxins.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antioxidants / metabolism
  • Aortic Valve Stenosis / blood
  • Aortic Valve Stenosis / pathology
  • Aortic Valve Stenosis / physiopathology
  • Biopsy
  • Cells, Cultured
  • Down-Regulation / drug effects*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Galectin 3 / blood
  • Galectin 3 / deficiency
  • Galectin 3 / pharmacology*
  • Heart / drug effects*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Myocardium / metabolism
  • Myocardium / pathology
  • Oxidative Stress / drug effects
  • Peroxiredoxins / biosynthesis*
  • Peroxiredoxins / genetics
  • Prospective Studies
  • Proteomics / methods

Substances

  • Antioxidants
  • Galectin 3
  • LGALS3 protein, human
  • Lgals3 protein, mouse
  • PRDX4 protein, human
  • Peroxiredoxins