Sex‐dependent expression of galectin‐1, a cardioprotective β‐galactoside‐binding lectin, in human calcific aortic stenosis

Abstract

We aimed to analyze sex-relateddifferences in galectin-1(Gal-1),a β-galactoside-bindinglectin, in aortic stenosis (AS) and its association with the inflammatoryand fibrocalcific progression of AS. Gal-1was determined in serum and aorticvalves (AVs) from control and AS donors by western blot and immunohistochemistry.Differences were validated by ELISA and qPCR in AS samples. In vitroexperiments were conducted in primary cultured valve interstitial cells (VICs).Serum Gal-1was not different neither between control and AS nor between menand women. There was no association between circulating and valvular Gal-1levels.The expression of Gal-1in stenotic AVs was higher in men than women, evenafter adjusting for confounding factors, and was associated with inflammation,oxidative stress, extracellular matrix remodeling, fibrosis, and osteogenesis. Gal-1(LGALS1) mRNA was enhanced within fibrocalcific areas of stenotic AVs, especiallyin men. Secretion of Gal-1was up-regulatedover a time course of 2, 4, and8 days in men's calcifying VICs, only peaking at day 4 in women's VICs. In vitro,Gal-1was associated with similar mechanisms to those in our clinical cohort.β-estradiolsignificantly up-regulatedthe activity of an LGALS1 promoter vectorand the secretion of Gal-1,only in women's VICs. Supplementation with rGal-1prevented the effects elicited by calcific challenge including the metabolic shiftto glycolysis. In conclusion, Gal-1is up-regulatedin stenotic AVs and VICs frommen in association with inflammation, oxidative stress, matrix remodeling, andosteogenesis. Estrogens can regulate Gal-1expression with potential implicationsin post-menopausewomen. Exogenous rGal-1can diminish calcific phenotypesin both women and men.