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Evaluation of the role of endothelin in aortic stenosis
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Edité par CCSD ; Elsevier/French Society of Cardiology -
International audience. IntroductionCalcified aortic stenosis (AS) is the most common acquired valvulopathy for which there is still no pharmacological treatment. Endothelin-1 (ET-1) is not only a powerful vasoconstrictor but also a pro-inflammatory and pro-fibrotic peptide whose role in AS remains unclear.ObjectiveThe aim of this study was to characterize the role of ET-1 in the aortic valve calcification.MethodValvular endothelial cells (VEC), isolated from human aortic valves, were cultured in a cell perfusion system to assess ET-1 production in different fluid flow shear stress conditions. In addition, valvular interstitial cells (VIC) were cultured in a pro-calcifying culture medium with or without small-molecule and monoclonal antibody ETA and ETB receptor antagonists or agonists receptor ETB IRL-1620 during 10 days. Aortic valves from rats were also cultured and stimulated with ET-1 antagonists. Calcium content was assessed using an o-cresolphtalein-based assay and fluorescence by Osteosens. VEC prepro-ET-1 and VIC osteogenic mRNA expression levels were evaluated by RTqPCR.ResultsTurbulent shear stress, mimicking the flow conditions at the aortic side of the valve increased VEC prepro-ET-1 mRNA expression level and ET-1 release as compared to laminar shear stress. Unexpectedly, calcium content of aortic valves was increased after blockade of ETB receptor and this effect was potentiated by concomitant blockade of ETA receptor. In contrast, ETB receptor agonist decreased calcium content. The mRNA expression of osteopontin, RUNX2, and BMP2 was similarly increased by ETA and ETB blockade.ConclusionThese results support a protective role of the endothelin system against the development of AS. Further studies are warranted to characterize the intracellular pathways and to confirm these results in in vivo models.
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