Abstract
Aortic valve stenosis (AVS) is the narrowing of the aortic valve (AV) opening caused by fibrosis and calcification. Despite this paradigm, no targeted medical therapy has proven to prevent, slow down or treat AVS. Using transcriptomic approach on human valvular interstitial cells (VIC) isolated from fibrocalcific and normal valves, our team has identified an enzyme X downregulated in fibro-calcific VIC. This enzyme X and its product Y have documented anti-calcification effects in other cell types than VIC. Our goal is to decipher the implication of this pathway on an in vitro model of human primary cultures of VIC in ostegenic conditions. Normal AV unsuitable for grafting and fibrocalcific AV from valve replacement (ATHERAO protocol) were collected. Levels of enzyme X in AV was assessing by histology and by Western Blot on tissue homogenate. VIC isolation was realized by enzymatic digestion of normal AV. Primary cultures were exposed to ostegenic media (OM) or control media with or without the product Y of the enzyme (1–1000 nM) during 7 days. Evaluation of calcification was realized by alizarin red staining, mRNA levels of calcification markers. We confirmed a differential expression of enzyme X on tissue by histology and by western blot (− 5.2 fold, P < 0.05) from fibro-calcific AV compared to those from control AV. In OM, enzyme X is decreased at the mRNA (− 5.2 fold, P < 0.05) and protein level (− 5.2 fold, P < 0.05) compared to control media. VIC treatments with product Y in presence of OM decrease the formation of calcium nodules in a dose dependent manner (− 5.2 fold, P < 0.05, vs OM) and mRNA levels for RUNX2 (− 2.4 fold, P < 0.05 vs OM), attenuating osteoblastic VIC differentiation. Our results demonstrate the involvement of this new pathway in an in vitro model of AVS by decreasing human VIC calcification and associated markers. Enzyme X is a potential innovative pharmacological therapeutic target in AVS.
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