Role for Galectin-3 in Calcific Aortic Valve Stenosis.
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.



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.



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.
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
J Rafael
JR
Sádaba
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Ernesto
E
Martínez-Martínez
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Vanessa
V
Arrieta
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Virginia
V
Álvarez
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Amaya
A
Fernández-Celis
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Jaime
J
Ibarrola
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Amaia
A
Melero
INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, Université de Lorraine French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France.
Patrick
P
Rossignol
Department of Physiology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain.
Victoria
V
Cachofeiro
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain natalia.lopez.andres@navarra.es.|INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, Université de Lorraine French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France.
Natalia
N
López-Andrés
D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000601:surgery; D018122:B7-1 Antigen / Q000378:metabolism; D001798:Blood Proteins; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D064113:CRISPR-Cas Systems; D002114:Calcinosis / Q000378:metabolism* / Q000601:surgery; D016022:Case-Control Studies; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D037161:Galectins; D055785:Gene Knockdown Techniques; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010006:Osteoblasts; D053495:Osteopontin / Q000378:metabolism; D010368:Pectins / Q000494:pharmacology; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018122:B7-1 Antigen; D001798:Blood Proteins; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D037502:Galectin 3; D037161:Galectins; D053495:Osteopontin; D010368:Pectins; D055758:SOX9 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C525718:BMP2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C428445:LGALS3 protein, human; C493709:RUNX2 protein, human; C527932:SOX9 protein, human; C506895:SPP1 protein, human; C439524:TNF protein, human; C586814:citrus pectin
aortic stenosis; calcification; galectin‐3; inflammation; valve; valvular interstitial cells