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

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.

• Authors: Stefano Menini, Carla Iacobini, Carlo Ricci, Claudia Blasetti Fantauzzi, Laura Salvi, Carlo M Pesce, Michela Relucenti, Giuseppe Familiari, Maurizio Taurino, Giuseppe Pugliese
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 100 Issue 3 Pg. 472-80 (Dec 01 2013) ISSN: 1755-3245 [Electronic] England
• PMID: 23975852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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