Role for Galectin-3 in Calcific Aortic Valve Stenosis

J Am Heart Assoc. 2016 Nov 4;5(11):e004360. doi: 10.1161/JAHA.116.004360.

Abstract

Background: Aortic stenosis (AS) is a chronic inflammatory disease, and calcification plays an important role in the progression of the disease. Galectin-3 (Gal-3) is a proinflammatory molecule involved in vascular osteogenesis in atherosclerosis. Therefore, we hypothesized that Gal-3 could mediate valve calcification in AS.

Methods and results: Blood samples and aortic valves (AVs) from 77 patients undergoing AV replacement were analyzed. As controls, noncalcified human AVs were obtained at autopsy (n=11). Gal-3 was spontaneously expressed in valvular interstitial cells (VICs) from AVs and increased in AS as compared to control AVs. Positive correlations were found between circulating and valvular Gal-3 levels. Valvular Gal-3 colocalized with the VICs markers, alpha-smooth muscle actin and vimentin, and with the osteogenic markers, osteopontin, bone morphogenetic protein 2, runt-related transcription factor 2, and SRY (sex-determining region Y)-box 9. Gal-3 also colocalized with the inflammatory markers cd68, cd80 and tumor necrosis factor alpha. In vitro, in VICs isolated from AVs, Gal-3 induced expression of inflammatory, fibrotic, and osteogenic markers through the extracellular signal-regulated kinase 1 and 2 pathway. Gal-3 expression was blocked in VICs undergoing osteoblastic differentiation using its pharmacological inhibitor, modified citrus pectin, or the clustered regularly interspaced short palindromic repeats/Cas9 knockout system. Gal-3 blockade and knockdown decreased the expression of inflammatory, fibrotic, and osteogenic markers in differentiated VICs.

Conclusions: Gal-3, which is overexpressed in AVs from AS patients, appears to play a central role in calcification in AS. Gal-3 could be a new therapeutic approach to delay the progression of AV calcification in AS.

Keywords: aortic stenosis; calcification; galectin‐3; inflammation; valve; valvular interstitial cells.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Aortic Valve / metabolism*
  • Aortic Valve / pathology*
  • Aortic Valve / surgery
  • Aortic Valve Stenosis / metabolism*
  • Aortic Valve Stenosis / surgery
  • B7-1 Antigen / metabolism
  • Blotting, Western
  • Bone Morphogenetic Protein 2 / metabolism
  • CRISPR-Cas Systems
  • Calcinosis / metabolism*
  • Calcinosis / surgery
  • Case-Control Studies
  • Cell Differentiation
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Female
  • Galectin 3 / genetics
  • Galectin 3 / metabolism*
  • Galectin 3 / pharmacology
  • Gene Knockdown Techniques
  • Heart Valve Prosthesis Implantation
  • Humans
  • In Vitro Techniques
  • Male
  • Osteoblasts
  • Osteopontin / metabolism
  • Pectins / pharmacology
  • Prospective Studies
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOX9 Transcription Factor / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • B7-1 Antigen
  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • CD68 antigen, human
  • Core Binding Factor Alpha 1 Subunit
  • Galectin 3
  • LGALS3 protein, human
  • RUNX2 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • SPP1 protein, human
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Osteopontin
  • citrus pectin
  • Pectins

Supplementary concepts

  • Aortic Valve, Calcification of