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(Circulation. 2009;119:2179-2187.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Mineralocorticoid Modulation of Cardiac Ryanodine Receptor Activity Is Associated With Downregulation of FK506-Binding Proteins

Ana María Gómez, PhD; Angélica Rueda, PhD; Yannis Sainte-Marie, PhD; Laetitia Pereira, PhD; Spyros Zissimopoulos, PhD; Xinsheng Zhu, PhD; Roxane Schaub, MD; Emeline Perrier, PhD; Romain Perrier, PhD; Céline Latouche, MS; Sylvain Richard, PhD; Marie-Christine Picot, MD, PhD; Frederic Jaisser, MD, PhD; F. Anthony Lai, PhD; Héctor H. Valdivia, MD, PhD; Jean-Pierre Benitah, PhD

From INSERM, U637 (A.M.G., A.R., L.P., E.P., R.P., S.R., J.-P.B.), Université Montpellier, France; INSERM, U772 (Y.S.-M., C.L., F.J.), Collège de France, Paris, France; Wales Heart Research Institute (S.Z., F.A.L.), Cardiff University School of Medicine, Cardiff, United Kingdom; Department of Physiology (X.Z., H.H.V.), University of Wisconsin Medical School, Madison, Wis; and Département de l’Information Médicale (R.S., M.-C.P.), Hôpital Lapeyronie, CHU Montpellier, France.

Correspondence to Jean-Pierre Benitah, Laboratoire de physiopathologie cardiovasculaire, INSERM U637, CHU Arnaud de Villeneuve, 34295 Montpellier, France. E-mail jean-pierre.benitah{at}inserm.fr

Received July 16, 2007; accepted March 3, 2009.

Background— The mineralocorticoid pathway is involved in cardiac arrhythmias associated with heart failure through mechanisms that are incompletely understood. Defective regulation of the cardiac ryanodine receptor (RyR) is an important cause of the initiation of arrhythmias. Here, we examined whether the aldosterone pathway might modulate RyR function.

Methods and Results— Using the whole-cell patch clamp method, we observed an increase in the occurrence of delayed afterdepolarizations during action potential recordings in isolated adult rat ventricular myocytes exposed for 48 hours to aldosterone 100 nmol/L, in freshly isolated myocytes from transgenic mice with human mineralocorticoid receptor expression in the heart, and in wild-type littermates treated with aldosterone. Sarcoplasmic reticulum Ca²⁺ load and RyR expression were not altered; however, RyR activity, visualized in situ by confocal microscopy, was increased in all cells, as evidenced by an increased occurrence and redistribution to long-lasting and broader populations of spontaneous Ca²⁺ sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex.

Conclusions— We suggest that in addition to modulation of Ca²⁺ influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca²⁺ release during diastole, which contributes to cardiac arrhythmia in heart failure.

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Clinical Summaries
Circulation 2009 119: 2125-2126. [Extract] [Full Text]