A New Role For AldosteroneMineralocorticoid Receptor Pathway In Mitral Valve Prolapse
Jaime F. Ibarrola Ulzurrun1, Amaia Garcia de la peña1, Rafael Sadaba1, Vanessa Arrieta1, Virginia Alvarez1, Amaya Fernandez1, Alicia Gainza1, Frederic Jaisser2, Natalia Lopez-Andres1.
1Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain, 2Cordeliers Research Centre INSERM U1138 Team 1, Paris, France.
Introduction and objectives. Mitral valve prolapse (MVP) is the most common cardiac valvular abnormality characterized by fibromyxomatous changes in the mitral leaflet tissue. There are currently no effective medical treatments capable of altering its course. Mineralocorticoid receptor antagonist (MRA) reduces myocardial fibrosis in animal models of MVP. In this study we investigated the effects of aldosterone (Aldo) in valvular interstitial cells (VICs) and valvular endothelial cells (VECs) isolated from MVP patients, as well as, the impact of MRA treatment in mitral valve structure and composition. Methods and results. Blood samples and mitral valves from 100 patients undergoing valve replacement for MVP were analyzed. VICs and VECs were isolated and treated with Aldo (10-10-10-8M) + - MRA (Spironolactone, 10-6M). In VICs and VECs treated with Aldo, VICs activation molecules/endothelial-mesenchymal transition (EndMT) markers, extracellular matrix proteins as well as proteoglycans production and secretion were measured by RT-PCR, Western Blot and ELISA. In VICs, Aldo treatment enhanced the activation markers and proteoglycans secretion. In VECs, Aldo induced EndMT and increased proteoglycans secretion. MRA blocked all the above effects. A cytokine array was used in cell supernatants of cell cultures treated with Aldo. Cardiotrophin-1 (CT-1) was identified as the most Aldo-up-regulated protein in VICs and VECs. Cells were then silenced for CT-1 and treated with Aldo. CT-1-knockdown VICs were resistant to Aldo-induced activation and proteoglycans secretion. However, in CT-1-silenced VECs Aldo maintained the induction of EndMT and proteoglycans. In MVP patients, positive correlations were found between circulating Aldo levels and valvular proteoglycans expression. Conclusion. Our data demonstrate that Aldo-enhanced VICs activation and proteoglycans secretion is mediated by CT-1. Moreover, Aldo induces EndMT and proteoglycans accumulation in VECs. Our results suggest that Aldo is a new player in the development of MVP. MRA could represent a novel therapeutic approach to delay the progression of MVP.
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