Influence of distinct cardiac-specific FKBP12.6 overexpression levels on cardiac function and [Ca2+]i cycling
2019
Cardiac ryanodine receptors (RyR2) have a key role in excitation-contraction coupling by releasing Ca 2+ from sarcoplasmic reticulum (SR). In cardiomyocytes, 2 FK506 binding protein (FKBP) isoforms have been shown to bind and to stabilize RyR2 opening: FKBP12 and FKBP12.6, the later having a stronger affinity for RyR2 despite its lower abundance. Cardiac-specific FKBP12.6 overexpressing mice have fewer arrhythmias induced by β-adrenergic stimulation than wild type (WT) mice, suggesting an implication of FKBP12.6 in an antiarrhythmic mechanism. Heart failure (HF) syndrome has a high incidence of arrhythmias, which may be explained by a decrease of FKBP isoform expression. The precise mechanism of the antiarrhythmic effect of FKBP12.6 overexpression remains unknown. To gain insight into this mechanism, we developed 2 transgenic mouse lines with cardiac-specific moderate- (TG1) and high- (TG2) FKBP12.6 overexpression levels. We characterized cardiac function, [Ca 2+ ]i cycling and its response to β-adrenergic stimulation in both mouse lines. TG1 and TG2 mice developed mild and marked cardiac hypertrophy, respectively, associated with basal cardiac function increase in TG1 mice only. In stimulated cardiomyocytes, [Ca 2+ ]i transient amplitude, measured by confocal microscopy, was higher in TG1 than in WT mice, without a significant difference in their SR Ca 2+ content. The effect of β-adrenergic stimulation (50nM isoproterenol) was attenuated in TG1 mice compared to WT mice, in association with the prevention of pro-arrhythmogenic Ca 2+ release events, such as Ca 2+ waves. In contrast, TG2 mice showed [Ca 2+ ]i handling characteristics similar to HF, with slower [Ca 2+ ]i transient relaxation. Interestingly, and contrary to HF, pro-arrhythmogenic Ca 2+ release events were also reduced in TG2. These results indicate that the level of FKBP12.6 overexpression has distinct effects on cardiac function and on Ca 2+ cycling and its response to β-adrenergic stimulation.
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