Open AccessRole for Galectin‐3 in Calcific Aortic Valve Stenosis
Author(s) -
Sádaba J. Rafael,
MartínezMartínez Ernesto,
Arrieta Vanessa,
Álvarez Virginia,
FernándezCelis Amaya,
Ibarrola Jaime,
Melero Amaia,
Rossignol Patrick,
Cachofeiro Victoria,
LópezAndrés Natalia
Publication year - 2016
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.116.004360
Subject(s) - medicine , proinflammatory cytokine , osteopontin , calcification , galectin 3 , osteocalcin , aortic valve , aortic valve stenosis , pathology , cancer research , inflammation , biology , alkaline phosphatase , biochemistry , enzyme
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 ( AV s) from 77 patients undergoing AV replacement were analyzed. As controls, noncalcified human AV s were obtained at autopsy (n=11). Gal‐3 was spontaneously expressed in valvular interstitial cells ( VIC s) from AV s and increased in AS as compared to control AV s. Positive correlations were found between circulating and valvular Gal‐3 levels. Valvular Gal‐3 colocalized with the VIC s 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 VIC s isolated from AV s, 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 VIC s 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 VIC s. 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 .