The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis

Cardiovasc Res. 2013 Dec 1;100(3):472-80. doi: 10.1093/cvr/cvt206. Epub 2013 Aug 23.

Abstract

Aims: Vascular calcification correlates with inflammation and plaque instability in a dual manner, depending on the spotty/granular (micro) or sheet-like/lamellated (macro) pattern of calcification. Modified lipoproteins trigger both inflammation and calcification via receptors for advanced lipoxidation/glycation endproducts (ALEs/AGEs). This study compared the roles of galectin-3 and receptor for AGEs (RAGE), two ALEs/AGEs-receptors with diverging effects on inflammation and bone metabolism, in the process of vascular calcification.

Methods and results: We evaluated galectin-3 and RAGE expression/localization in 62 human carotid plaques and its relation to calcification pattern, plaque phenotype, and markers of inflammation and vascular osteogenesis; and the effect of galectin-3 ablation and/or exposure to an ALE/AGE on vascular smooth muscle cell (VSMC) osteogenic differentiation. While RAGE co-localized with inflammatory cells in unstable regions with microcalcification, galectin-3 was expressed also by VSMCs, especially in macrocalcified areas, where it co-localized with alkaline phosphatase. Expression of galectin-3 and osteogenic markers was higher in macrocalcified plaques, whereas the opposite occurred for RAGE and inflammatory markers. Galectin-3-deficient VSMCs exhibited defective osteogenic differentiation, as shown by altered expression of osteogenic transcription factors and proteins, blunted activation of pro-osteoblastogenic Wnt/β-catenin signalling and proliferation, enhanced apoptosis, and disorganized mineralization. These abnormalities were associated with RAGE up-regulation, but were only in part prevented by RAGE silencing, and were partially mimicked or exacerbated by treatment with an AGE/ALE.

Conclusion: These data indicate a novel molecular mechanism by which galectin-3 and RAGE modulate in divergent ways, not only inflammation, but also vascular osteogenesis, by modulating Wnt/β-catenin signalling, and independently of ALEs/AGEs.

Keywords: Galectin-3; Inflammation; RAGE; Vascular calcification; Wnt/β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alkaline Phosphatase / metabolism
  • Animals
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Stenosis / genetics
  • Carotid Stenosis / metabolism*
  • Carotid Stenosis / pathology
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Galectin 3 / deficiency
  • Galectin 3 / genetics
  • Galectin 3 / metabolism*
  • Glycation End Products, Advanced / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Osteogenesis*
  • Oxidative Stress
  • Plaque, Atherosclerotic
  • RNA Interference
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction
  • Transfection
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / pathology
  • Wnt Signaling Pathway

Substances

  • Galectin 3
  • Glycation End Products, Advanced
  • Inflammation Mediators
  • LGALS3 protein, human
  • Lgals3 protein, mouse
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Alkaline Phosphatase