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

INSERM, U637, Université Montpellier, France.
Circulation (Impact Factor: 14.43). 05/2009; 119(16):2179-87. DOI: 10.1161/CIRCULATIONAHA.108.805804
Source: PubMed


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.
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 Ca(2+) 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 Ca(2+) sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex.
We suggest that in addition to modulation of Ca(2+) influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca(2+) release during diastole, which contributes to cardiac arrhythmia in heart failure.

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Available from: Celine Latouche, Sep 22, 2015
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    • "Furthermore, it was found that the dendritic branching could increase in number by suppressing the calcineurin molecule [27,28]. The FK506-binding proteins (FKBP12 and 12.6) are involved in a regulation of ryanodine receptors that control the calcium ion in the sarcoplasmic reticulum of a heart, and the treatment of FK506 loosens their binding and calcium is released from the sarcoplasmic reticulum as a result [29]. In addition, when IP3R is inhibited in association with the control of neurite outgrowth by calcium, the neurite outgrowth was suppressed in the early stage, whereas the inhibition of calcium-induced calcium release by ryanodine receptor suppresses the neurite outgrowth in the later stage. "
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    ABSTRACT: This study investigated the Jurkat T cell line expresses cytotoxicity when treated with different concentrations of FK506, and analyzed the expression pattern of microRNA when stimulated by FK506 using the microRNAs microarray, as well as the expression pattern of a gene that is related to the differentiation, activation and proliferation of T cells after being affected by the change of microRNAs. To investigate the effects of FK506 on microRNA expression, we purified total RNA of Jurkat cells treated with 20 µM FK506 for 72 hours and used to analyze microRNA profiling by using Agilent's chip. These results demonstrated that treatment with FK506 markedly induced the down-regulation of 20 microRNAs as well as the up-regulation of 20 microRNAs in a time-dependent manner. The genes that down-regulated by FK506 include let-7a(*), miR-20a(*), and miR-487a. Otherwise miR-202, miR-485-5p, and miR-518c(*) are gradually up-regulated in expression. Sanger Institute and DAVIDs bioinformatics indicated that microRNAs regulated the several transcriptomes including nuclear factor of activated T cell-related, T cell receptor/interleukin-2 signaling, and Ca(2+)-calmodulin-dependent phosphatase calcineurin pathways. As a result of treating FK506 to a Jurkat cell line and running the microRNA microarray, it was found that FK506 not only took part in the suppression of T cell proliferation/activation by inhibiting calcineurin in Jurkat apoptosis, but also affected the microRNAs that are involved in the regulation of various signal transduction pathways.
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    • "Thus, RU-mediated blockade of these important processes likely also improves calcium handling and overload in hearts subjected to I/R. This assertion is supported by previous findings that aldosterone/MR activation induces cardiomyocyte ionic remodelling by modulating potassium and L-type calcium channel activity [31] [32], T-type calcium channel expression [33], and ryanodine receptor activity [34]. Changes in these calcium handling proteins have been reported to lead to important consequences in the control of calcium signaling, modulation of calcium transients, sarcoplasmic reticulum diastolic leaks, and promotion of rhythm disorders that can be corrected by aldosterone/MR antagonism [35] [36] [37]. "
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    • "We found some lines of evidence supporting this hypothesis. We saw that aldosterone, a neurohormone involved in HF, (1) activates LTCC expression (Bénitah and Vassort, 1999), (2) increases diastolic Ca 2+ release by decreasing the expression of the RyR accessory proteins FKBP12 and 12.6 (Gomez et al., 2009), and (3) decreases the expression of the channel responsible for the transient outward potassium current (I to ) secondarily to an increase in [Ca 2+ ] i and activation of Cn (Bénitah et al., 2003; Perrier et al., 2004), thereby recapitulating some of the outcomes of HF (Bénitah et al., 1993, 2002; Gómez et al., 1997; Marx et al., 2000). Interestingly, the increase in LTCC expression precedes cell hypertrophy (Perrier et al., 2003). "
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