Role for Galectin‐3 in Calcific Aortic Valve Stenosis

Abstract

BackgroundAortic 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 ResultsBlood 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.ConclusionsGal‐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.

Serum biomarkers in valvular heart disease

“…Interestingly, in vitro and preclinical in vivo studies suggest that Gal-3 may have a role in the disease process at the valve level in AS,74 but further studies are required to examine this further.…”

Galectin-3 as a novel biotarget in cardiovascular alterations associated to development of severe aortic stenosis

“…Gal-3 expression has been recently reported in VICs from aortic valves in patients undergoing aortic valve replacement 32 . Moreover, Gal-3 co-localized with the expression of osteogenic and inflammatory markers in human aortic valves 32 .…”

“…Furthermore, Gal-3 modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells contributing to the plasma membrane retention and exerting a pro-angiogenic function 39 . In VICs from aortic valves, Gal-3 also increases the secretion of pro-inflammatory and pro-fibrotic markers as well as the expression of calcification markers 32 .…”

“…The expression of this lectin has been reported in many tissues, including heart, vessels and kidney 28 . Moreover, Gal-3 is expressed in many cell types of the cardiovascular system such as cardiac fibroblasts 29 , vascular smooth muscle cells 30 , endothelial cells 31 , VICs 32 and inflammatory cells 33 . Gal-3 is involved in numerous physiological and pathological processes some of which, inflammation and fibrosis, are pivotal contributing to pathophysiological mechanisms in the development and progression of HF.…”

Hydrostatic pressure suppresses fibrotic changes via Akt/GSK-3 signaling in human cardiac fibroblasts

“…The sequences of the specific primers were as follows: ACTA2 (forward, 5′‐ ATTGCCGACCGAATGCAGA ‐3′; reverse, 5′‐ ATGGAGCCACCGATCCAGAC ‐3′), col1A1 (forward, 5′‐ CCCGGGTTTCAGAGACAACTTC ‐3′; reverse, 5′‐ TCCACATGCTTTATTCCAGCAATC ‐3′), col3A3 (forward, 5′‐ CTTCTCTCCAGCCGAGCTTC ‐3′; reverse, 5′‐ TGGAGGTTAGTGGGAGCATC ‐3′), MMP‐1 (forward, 5′‐ ACATGAGTCTTTGCCGGAGG ‐3′; reverse, 5′‐ AACAAGGTTGACTTTATTCCAAACA ‐3′), IL‐6 (forward, 5′‐ AGTTCCTGCAGAAAAAGGCAAAG ‐3′; reverse, 5′‐ CATTTGCCGAAGAGCCCTCA ‐3′), TNF‐ α (forward, 5′‐ CACTGAAAGCATGATCCGGG ‐3′; reverse, 5′‐ CTGGGGAACTCTTCCCTCTGG ‐3′), and GAPDH (forward, 5′‐CCCATCACCATCTTCCAGGAGCG‐3′; reverse, 5′‐GGCAGGGATGATGTTCTGGAGAGCC‐3′) (Sádaba et al. ).…”