© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Sarcoplasmic reticulum calcium release function and FK binding proteins in heart failure: another piece of a complex jigsaw
Imperial College School of Medicine, National Heart and Lung Institute, Cardiac Medicine, Dovehouse Street, London SW3 6LY, UK
* Tel.: +44-20-7352-8121, ext. 3322; fax: +44-20-7351-8145 c.terracciano{at}ic.ac.uk
Received 16 August 2000; accepted 16 August 2000
See article by Ono et al. [1] (pages 323–331) in this issue.
Dysfunction is a complex phenomenon in heart failure. Most cardiac structures are altered and functional relationships are disrupted. A global picture of the pathophysiology of heart failure is not yet available. However, many studies showing modifications of different aspects of cardiac physiology have been carried out and more pieces of this complex jigsaw are revealed. Amongst these, the paper by Ono et al., published in the present issue of Cardiovascular Research [1], focuses on the role of FK binding proteins (FKBPs) in heart failure.
FKBPs are immunophilin proteins associated with the SR Ca release channel (ryanodine receptor (RYR)), which have attracted attention because of their possible involvement in the pathophysiology of cardiac muscle. It has been suggested that, in muscle, FKBP stabilizes RYR function and this could be involved in the gating of the RYR [2,3]. Disruption of this binding leads to modifications of the channel properties that manifest as appearances of sub-conductance states and/or increased open probability (Po) [3]. The paper by Ono et al. [1] is the last of a trilogy from the same research group, which has focused on the importance of the RYR–FKBP relationship in heart failure. The first paper [4] showed that, in heart failure, polylysine-induced Ca release from SR vesicles was decreased, suggesting an impaired gating function of the RYR. The authors subsequently observed that the ratio between FKBP12.6 (the cardiac isoform of FKBP) and RYR in heart failure was reduced compared with normal hearts and that this was associated with an abnormal Ca leak through the RYR [5]. In the present study the authors have combined the previous observations in the hypothesis that the altered gating function of RYR is caused by a defect in FKBP. Aspects investigated include the role of the dissociation of FKBP from RYR on Ca release and the amount of FKBP in SR vesicles isolated from normal and failing hearts. The major finding is that, in heart failure, there is a dramatic reduction in FKBP. This corresponds to the observation that application of the immunosuppressant agent FK506, to produce dissociation of FKBP12.6 from RYR in normal hearts, did not cause any further reduction in the rate of Ca release from the SR vesicles isolated from failing hearts. This suggests that in heart failure the regulation of FKBP on RYR is absent, resulting in abnormal and maximal Ca leak. The authors conclude that the modification of the polylysine-induced SR Ca release in heart failure is due to a reduced amount of FKBP.
In all three studies heart failure was induced by pacing in dogs. The authors have characterized the haemodynamic aspects of this model and showed a consistent systolic and diastolic dysfunction of the failing hearts under investigation. Such a model, used previously by other groups (e.g [6,7]), represents a well-established technique. However, the same authors consider some of the problems in comparing this model with the chronic failing condition observed in human pathophysiology.
Considering the evidence from this and other studies, it may be concluded that in heart failure a reduction in FKBP is responsible for a modification of SR Ca release function, therefore causing pathophysiological changes. I would like to discuss two points: the role of FKBP in the impairment of SR Ca release function and the ability of this impairment to affect Ca regulation and therefore contraction in the intact cardiac muscle cell.
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1 FKBP and SR Ca release function: the macromolecular complex |
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 Top 1 FKBP and SR... 2 SR Ca release...References |
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The functional link between FKBP binding and the SR Ca release channel has been widely studied. In a recent paper, Marx et al. [8] described a macromolecular complex in cardiac muscle formed by RYR2, FKBP12.6, protein kinase A (PKA), protein phosphatases PP1 and PP2A and mAKAP (anchoring structure). The authors suggest that phosphorylation could increase the dissociation between RYR and FKBP12.6 therefore influencing SR Ca release. The link between the regulatory effect of RYR–FKBP binding with phosphorylation is intriguing because it provides an explanation for the reduced response to β-stimulation in heart failure and a phosphorylation-linked regulation of the SR Ca release function. In that paper and in a subsequent review [9] the authors proposed a model where, in non-failing hearts, a discrete phosphorylation of the complex due to β-stimulation could increase the Po of the channel and so increase the gain of excitation–contraction coupling (i.e. more Ca release for the same cytoplasmic Ca trigger). The hyperphosphorylated state of the failing myocardium would offset this regulation to its maximum so that β-stimulation would not produce any further increase in Po (blunt β-stimulation response). The maximum RYR–FKBP12.6 dissociation would also increase Ca leak from the SR to produce a reduction in the SR Ca content and increased diastolic [Ca]. Thus, the authors conclude, abnormal interactions in the macromolecular complex could be responsible for systolic and diastolic dysfunction in heart failure.
This very exciting hypothesis seems to explain many aspects of the behaviour of the failing heart. However, some aspects of this phenomenon remain unclear. Firstly, RYR itself has been shown to be down-regulated, although this finding is not consistent in different studies and models of heart failure [10]. In addition, not all the studies could completely confirm the role of FKBP12.6 in regulating the function of the cardiac SR Ca release channel. Timerman et al. [11], for example, showed that in cardiac muscle, application of FK590 (an analog of FK506) did not have any effect on Ca release channel activity. Studies performed on tissue from FKBP12-deficient mice showed that the absence of the skeletal muscle isoform FKBP12 resulted in abnormal gating properties of both RyR1 and RyR2, yet only cardiac dysfunction was observed [12]. This suggests that the specificity of the isoforms and their role on RYR regulation require further investigation.
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2 SR Ca release and cytoplasmic Ca regulation: functional consequences for contraction |
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Top1 FKBP and SR...2 SR Ca release...References |
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Impaired SR Ca release alone may not be able to explain a dysfunction in Ca handling in normal myocardium. There is evidence that affecting the gating function of RYR does not result in a permanent change in peak contraction of rat cardiac myocytes. The SR seems to be able to regulate its release mainly by changing the amount of SR Ca content [13]. Given these results and assuming no difference between species, the effects on Ca cycling described by the macromolecular complex model are difficult to support unless associated with the dysfunction of other Ca regulatory mechanisms [14].
However, some experimental data support the macromolecular complex model in part. McCall et al. [15] showed that FK506 was able to produce an increase in SR Ca content and an increase in the frequency of Ca ‘sparks’ in intact rat cardiac myocytes. FK506 was able to produce a maintained increase in peak contraction and peak Ca transient. These data could be explained by an increased dissociation of FKBP from RYR leading to an increased SR Ca release and increased contractility as suggested for a discrete activation of the macromolecular complex. However, effects of FK506 on other Ca cycling mechanisms and in particular on the Na/Ca exchanger function were found. In addition there was no evidence that if the dissociation of FKBP from RYR was greater this could produce the Ca transient observed in heart failure, which has been reported to be smaller and slower than control [10].
Another effect predicted by the macromolecular complex model in heart failure is a decrease in SR Ca content. This point deserves special consideration for two reasons: (1) luminal Ca itself can regulate the gating of RYR (e.g. [16]). Thus, it is possible that if SR Ca content is decreased, an increased Po induced by RYR–FKBP dissociation can be overruled. There could be a degree of autoregulation in the complex itself. (2) In some studies the SR Ca content in heart failure has been found to be unaffected. Gomez et al. [17] for example, in a model of spontaneous heart failure in rats, showed that failing animals had a normal SR Ca content and the properties of Ca sparks were unchanged suggesting normal Ca release from the SR. Similarly, in a model of heart failure in rabbits, caffeine-induced Ca release was unchanged also suggesting that SR Ca content was not different [18]. However, Sen et al. [19] have reported reduced caffeine-induced contractions in the failing human heart, suggestive of a decreased SR Ca content, particularly in ischaemic cardiomyopathy. The same authors found that, in patients with idiopathic dilated cardiomyopathy, heart failure was associated with a much less severe decrease in the SR Ca content compared with the ischaemic condition. Whether an abnormal leakage of Ca and, indeed the RYR–FKBP dissociation itself, is present in every form of heart failure and with the same functional relevance remains unclear.
How then does dissociation of FKBP12.6 to RYR produces abnormalities of Ca regulation? Some authors have suggested that this could be due to the inhibition of ‘coupled gating’. The inability of the SR Ca release channels to open and close simultaneously could provoke an inefficient and prolonged Ca transient [2,9].
Finally, and most importantly, this phenomenon in heart failure should be considered in a more global scenario where many Ca regulatory proteins are also affected (e.g. [10]). Down-regulation of SERCa and phospholamban and a functional inadequacy of the SR Ca uptake, together with changes in the function of the Na/Ca exchanger [20], should especially be considered. In the same model of pacing-induced heart failure in the dog when excitation–contraction coupling was studied at a cellular level, a smaller and dramatically prolonged Ca transient was found [6]. In that paper O'Rourke et al. showed a clear reduction in SR Ca release associated with slower decline of cytoplasmic [Ca]. This was coupled with the findings of reduced expression and function of SERCa and phospholamban and increased expression of the Na/Ca exchanger. Impairment in SR Ca uptake could certainly be responsible for a slower Ca decline and a reduction in SR Ca content whereas an enhanced Na/Ca exchanger could partially compensate for these defects. Dysfunction of SR Ca uptake could be responsible for the lack of autoregulation of the SR, leading to inefficient SR function. In this context, an impaired SR Ca release could play an important functional role in excitation–contraction coupling.
In conclusion, the paper by Ono et al. [1] represents an interesting step in the understanding of the malfunction of SR Ca release in heart failure. It produces clear evidence of the disrupted relationship between FKBP and RYR. In heart failure the delicate interactions between SR Ca release complex molecules could transform a highly specialized regulatory mechanism into a structure ‘out of control’. However, these results need to be interpreted in a wider picture of dysfunction. Many structures are affected to different degrees (depending on the failing conditions considered) by the pathophysiological events and together can lead to heart failure.
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References |
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