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Mineralocorticoid modulation of cardiac ryanodine receptor activity is associated with downregulation of FK506-binding proteins

Gomez, Ana Maria, Rueda, Angelica, Sainte-Marie, Yannis, Pereira, Laetitia, Zissimopoulos, Spyros, Zhu, Xinsheng, Schaub, Roxane, Perrier, Emeline, Perrier, Romain, Latouche, Celine, Richard, Sylvain, Picot, Marie-Christine, Jaisser, Frederic, Lai, Francis Anthony, Valdivia, Hector H. and Benitah, Jean-Pierre 2009. Mineralocorticoid modulation of cardiac ryanodine receptor activity is associated with downregulation of FK506-binding proteins. Circulation 119 (16) , pp. 2179-2187. 10.1161/CIRCULATIONAHA.108.805804

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: aldosterone; calcium; ryanodine receptor; hormones; ion channels; arrhythmia
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0009-7322/ (accessed 19/02/2014).
Publisher: American Heart Association
ISSN: 0009-7322
Date of First Compliant Deposit: 30 March 2016
Last Modified: 27 Mar 2020 02:37
URI: http://orca-mwe.cf.ac.uk/id/eprint/27712

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