Aortic Valve Calcification Is Induced by the Loss of ALDH1A1 and Can Be Prevented by Agonists of Retinoic Acid Receptor Alpha: Preclinical Evidence for Drug Repositioning
Abstract
BACKGROUND: To date, the only effective treatment of severe aortic stenosis is valve replacement. With the introduction of transcatheter aortic valve replacement and extending indications to younger patients, the use of bioprosthetic valves (BPVs) has considerably increased. The main inconvenience of BPVs is their limited durability because of mechanisms similar as the fibro-calcifying processes observed in native aortic stenosis. One of the major gaps of the field is to identify therapeutic targets to prevent or slow the fibro-calcifying process leading to severe and symptomatic aortic stenosis. METHODS: Explanted valves were collected from patients and organ donor hearts. A comparative transcriptomic analysis was performed on valvular interstitial cells (VIC) obtained from calcified (bicuspid and tricuspid) versus control valves. The mechanisms and consequences of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) downregulation were analyzed in VIC cultures from control human aortic valves. ALDH1A1 was inhibited or silenced and its impact on osteogenic marker expression and calcification processes assessed in VIC. The effect of all-trans retinoic acid on calcification was tested on human VIC cultures and on 2 animal models: the model of subcutaneous implantation of bovine pericardium in rats and the model of xenograft aortic valve replacement in juvenile sheep. RESULTS: Transcriptome analysis of human VIC identified ALDH1A1 as the most downregulated gene in VIC from calcified versus control valves. In human VIC, ALDH1A1 expression is downregulated by TGF-β in a SMAD2/3-dependent manner. ALDH1A1 inhibition promotes an osteoblast-like VIC phenotype and increases calcium deposition through inhibition of retinoic acid receptor alpha signaling. Conversely, VIC treatment with retinoids decreases calcium deposition and attenuates VIC osteoblast activity. Last, all-trans retinoic acid inhibits calcification development of aortic BPV in both in vivo models and improves aortic valve echocardiographic parameters in the xenograft sheep model. CONCLUSIONS: These results show that ALDH1A1 is downregulated in calcified valves, hence promoting VIC transition into an osteoblastic phenotype. Retinoic acid receptor alpha agonists, including all-trans retinoic acid through a drug repositioning strategy, represent a promising and innovative pharmacological approach to prevent calcification of native aortic valves and BPV.
Article Details
Authors (23)
Mickael Rosa
Annabelle Dupont
David M. Smadja
Jérôme Soquet
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Johan Abdoul
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Thibault Pamart
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Flavien Vincent
Cardiology, University Hospital Lille, France (F.V., E.V.B.).
Christina Le Tanno
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Eloise Borowczak
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Timothée Bigot
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Alexandre Ung
Bertrand Vaast
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Melanie Daniel
University of Lille, Inserm, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Ramadan Jashari
European Homograft Bank, Brussels, Belgium (R.J.).
Frédéric Mouquet
Hemostasis and Transfusion Department (A.D., A.U., B.V., M.D., F.M., S.S.), CHU Lille, France.
Cedric Delhaye
Department of Interventional Cardiology for Coronary, Valves and Structural Heart Diseases (F.V., C.D., E.V.B.), CHU Lille, France.
Yoann Sottejeau
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Jeanne Rancic
Delphine Corseaux
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Francis Juthier
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID (M.R., A.D., J.S., J.A., T.P., F.V., C.L.T., E.B., T.B., A.U., B.V., M.D., Y.S., D.C., F.J., B.S., S.S., E.V.B.), CHU Lille, France.
Bart Staels
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Sophie Susen
Eric Van Belle
Department of Cardiology, Institut Cœur Poumon, Centre Hospitalier Universitaire Lille, Lille, France