Cardiovascular Research

Cardiovascular Research 2000 45(1):245-252; doi:10.1016/S0008-6363(99)00338-7
© 2000 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

Regulation of sarcoplasmic reticulum Ca²⁺-ATPase and phospholamban in the failing and nonfailing heart

U Ravens^* and D Dobrev

Department of Pharmacology and Toxicology, Medical School of the Dresden University of Technology, Karl-Marx-Straße 3, D-01109 Dresden, Germany

^* Corresponding author. Tel.: +49-351-883-2830; fax: +49-351-883-2832 ravens{at}rcs.urz.tu-dresden.de

KEYWORDS Calcium (cellular); Genetic code; Heart failure; SR (function); Ventricular function

	1 Introduction

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
The mammalian organism responds to chronic pressure and volume overload of the heart with a plethora of adaptive changes that consist of resetting of the neurohumoral homeostasis on a more general level and of structural remodeling and functional alterations on the cellular level. These latter changes include electrophysiological properties as exemplified by prolongation in action potential duration and rhythm disturbances considered responsible for sudden cardiac death as well as depression in contractile function of individual myocytes. Since calcium ions (Ca²⁺) play a pivotal role in cardiac excitation–contraction coupling, contractile dysfunction has been interpreted as a defect in Ca²⁺-handling proteins of the sarcoplasmic reticulum (SR) at the subcellular level.

This survey begins with a brief outline of cardiac excitation–contraction coupling and the functional role of the SR Ca²⁺-ATPase and its regulatory protein phospholamban. It continues with a summary of a frequently cited paper on the modulatory changes in these two Ca²⁺ homeostasis regulating proteins in human heart failure [1] and it will then discuss the confirmatory and controversial issues published since that seminal work appeared. The review will conclude with recently defined deficiencies at other subcellular sites. In its course, the reader is frequently referred to the excellent reviews of our current knowledge on the topic, which were compiled in the 1998 focused issue of this journal [2–7].

	2 Cardiac excitation–contraction coupling

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
Contraction of heart muscle is initiated by electrical excitation of the plasmalemma followed by the typical long lasting cardiac action potential. Calcium entering the myocytes during the plateau phase of the action potential mainly via voltage sensitive L-type Ca²⁺ channels serves as a trigger for further release of Ca²⁺ from the major intracellular store, the SR. The free cytosolic Ca²⁺ concentration ([Ca²⁺]_i) determines the extent of activation of contractile proteins and thus regulates force development. For relaxation, [Ca²⁺]_i must be lowered again and this is initiated mainly by reuptake of Ca²⁺ into the SR. Release and uptake of Ca²⁺ occur in different structural entities of the SR. The special ryanodine-sensitive Ca²⁺ release channels are localized within close vicinity of the sarcolemma, whereas the energy-consuming Ca²⁺-ATPase for pumping Ca²⁺ into the lumen is localized in the longitudinal part of the SR. For maintenance of cellular Ca²⁺ homeostasis Ca²⁺ influx must be compensated by Ca²⁺ removal from the cell via the Na⁺–Ca²⁺ exchanger [8]. In addition, mitochondria have a large capacity for Ca²⁺ uptake and release, however their contribution to the [Ca²⁺]_i transient during an individual contractile cycle is less clear [9,10].

Any one of these subprocesses is a potential target of pathological changes in heart failure. Findings in muscle strips or single myocytes isolated from failing human hearts include: prolongation of action potential duration [4,11,12], reduced amplitude of the intracellular [Ca²⁺]_i transients [13–15], impaired force development particularly at high frequencies of stimulation [11,16], and slowed relaxation [15,17]. The conspicuous relaxation abnormalities in heart failure have been related to impairment of cellular calcium handling proteins [18] involving quantitative and/or functional changes. This interpretation has led to a great amount of work devoted to the study of the cardiac SR Ca²⁺-ATPase (SERCA2) and its regulatory protein phospholamban (for recent reviews, see Refs. [2,5,19]).

Three Ca²⁺-ATPase genes encode for the large proteins that pump Ca²⁺ into SR or endoplasmic reticulum for later release [20]. The two isoforms of SERCA1 are expressed in adult (SERCA1a) and neonatal (SERCA1b) fast twitching skeletal muscle. The two isoforms of SERCA2 are found in slowly contracting muscles such as cardiac muscle (SERCA2a) and smooth muscle, and slow twitch skeletal muscle (SERCA2b). Finally, SERCA3 existing in a single isoform only is the subtype expressed in other types of muscle and nonmuscle cells. The functional significance of the cardiac SERCA2 has been demonstrated in transgenic mice where overexpression of the gene product enhances cardiac performance [21–23]. Interestingly, myocardial contractile function is also enhanced when the fast twitch skeletal muscle isoform SERCA1a is selectively overexpressed in murine hearts, and this is associated with faster shortening and relaxation rates in isolated myocytes indicating that the isoform SERCA1a can substitute for the endogenous SERCA2a [24].

The activity of the SR Ca²⁺ pump is regulated by the small, 52-amino-acid protein phospholamban of which no subtypes are known (for review, see Ref. [19]). In its basal unphosphorylated state, phospholamban inhibits the SR Ca²⁺-ATPase by decreasing the affinity of the calcium pump for Ca²⁺ [25–27], whereas in its phosphorylated state, it enhances the activity of SR Ca²⁺-ATPase [25] via an increase in affinity of the pump for calcium without change in maximum velocity of the enzyme [28,29]. Phosphorylation of myocardial phospholamban is catalysed by several enzymes including calcium/calmodulin-dependent protein kinase and cAMP-dependent protein kinase A, with distinct sites of phosphorylation by either kinase (for review, see Ref. [30]). The inhibitory function of unphosphorylated phospholamban on SR Ca²⁺-ATPase can also be demonstrated in transgenic mice in which ablation of the phospholamban gene is accompanied by an increase in the SR Ca²⁺-ATPase affinity for calcium with enhanced rates of contraction and relaxation as well as increased pump rate [28,31–33], whereas overexpression of phospholamban gene results in depressed SR Ca²⁺-ATPase affinity for calcium and decreased myocardial performance [34].

While contractile proteins demonstrate an isoform shift in the development of heart failure [35–37] (for review, see Ref. [38]), this has not been observed for SERCA2a or phospholamban [39].

	3 Summary of a frequently cited paper on changes in SR protein expression in end-stage heart failure [1]

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
Animal models of hypertrophy and failure reveal that mRNA of both SERCA2 and phospholamban are reduced (Table 1; for review, see Ref. [39]) and evidence for similar alterations in end-stage human heart failure had been published by several groups before the study of Linck et al. [1] (see Table 2). The general notion was that reduced mRNA levels implied reduced protein levels as well, and for SERCA2, this expectation had in fact been confirmed [40]. On the other hand, impaired Ca²⁺ uptake into the SR, i.e. impaired function, does not necessarily indicate decreased protein levels of SERCA2 and/or phospholamban because the function of these proteins is regulated by the extent of phospholamban phosphorylation (see above) which can be downregulated by different and independent adaptations as for instance changes in the β-adrenoceptor signaling cascade (for review, see Ref. [41]). Based on these considerations, experiments were designed in which mRNA and protein contents were determined in parallel in the same tissue samples and the results were analysed separately for ischemic cardiomyopathy and idiopathic dilated cardiomyopathy. Quantification of mRNA by hybridization of total RNA with ³²P-labeled cDNAs for rat SERCA2 and human phospholamban revealed that mRNA for SERCA2 was reduced by 50% and for phospholamban by 30% in failing as compared with nonfailing control hearts, whereas the concentrations for these two proteins as measured with specific antibodies were not different. The authors suggested that the apparent discrepancy between constant protein levels and yet reduced SR Ca²⁺ uptake function which is assumed as causal for impaired relaxation in heart failure could be due to functional modification, e.g., altered phosphorylation, of SR proteins. — Besides its specific topic, the work by Linck et al. [1] carries the more general message of a big caveat that extrapolation from cardiac mRNA levels to protein expression may be misleading.

View this table: [in this window] [in a new window]   Table 1 Altered gene expression of calcium handling proteins in end-stage animal heart failure

 

View this table: [in this window] [in a new window]   Table 2 Altered gene expression of calcium handling proteins in end-stage human heart failure

 

	4 SR calcium pump and phospholamban in the failing animal heart

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
While biochemical studies in human failing myocardium are limited to the end-stages of the disease, various animal models of hypertrophy and heart failure have been developed in order to study also discrete changes. Frequently employed models attempt to simulate ischemia-induced, tachycardia-induced, and pressure-overload-induced heart failure (for review, see Ref. [42]). In these different animal models of heart failure, expression of myocardial mRNA (and sometimes also of protein levels) for SERCA2 and phospholamban have been studied, but far less information is available about the expression of phospholamban than about the respective expression of SR Ca²⁺-ATPase (Table 1). Nevertheless, the results from these studies are controversial and appear to be related to the particular model of heart failure used.

For instance, in the rat model of chronic myocardial infarction studied several weeks after occlusion of the left coronary artery, myocardial mRNA and protein levels of the SR Ca²⁺-ATPase are reported to be decreased [43,44] or unchanged [45,46], and no concomitant change in mRNA or protein content of phospholamban has been detected [45]. This experimental model is considered to represent ischemic cardiomyopathy.

Chronic, high-frequency pacing of rabbit, pig or dog hearts causes tachycardia-induced heart failure that apparently does not affect the SR Ca²⁺-ATPase mRNA levels as reported in earlier studies [47]. However, more recent results suggest a significant decrease in SR Ca²⁺-ATPase mRNA levels [48–50], and, when investigated, protein level is also significantly decreased [48,51]. For phospholamban, mRNA is found to be unchanged [47,48], whereas protein level is decreased [51]. It must be pointed out, however, that here, mRNA and protein levels have been investigated neither in the same probes nor in the same study.

Pressure-overload-induced heart failure develops after aortic banding. In this model mRNA and protein levels for SR Ca²⁺-ATPase are consistently depressed in rat and guinea pig models [52–59]. Interestingly, in most studies this change is accompanied by concomitant decrease in mRNA for phospholamban [53,57] and phospholamban protein level [52,58] with one controversial report of unchanged mRNA levels [56].

	5 SR calcium pump and phospholamban in the failing human heart

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
Although animal models of cardiac hypertrophy and failure are highly valued because many problems cannot be solved in man for obvious ethical reasons, care must be taken when extrapolating results from different species to man. Therefore, experiments in human isolated myocardium are indispensible despite the difficulties of obtaining normal controls. In this context, many groups have studied putative failure-induced alterations in mRNA and/or protein levels of SR Ca²⁺-ATPase and/or phospholamban in human cardiac tissue (Table 2).

All studies investigating mRNA for SR Ca²⁺-ATPase have yielded strikingly consistent results of lower mRNA levels in failing than in nonfailing myocardium irrespective of the underlying pathogenesis, i.e., ischemic cardiomyopathy or idiopathic dilated cardiomyopathy [1,40,60–65]. The same holds true for mRNA levels of phospholamban which are also depressed in failing as compared with nonfailing tissue [1,62–66]. Because of the early assumption that protein expression always parallels mRNA expression, many authors have omitted simultaneous determinations of mRNA and protein levels in the same sample. Measuring only protein levels of SERCA2, the group working with Hasenfuss finds them to be decreased in heart failure [67–70] and this has been confirmed in another study together with decreased mRNA levels [40]. In contrast, seven other studies have not detected changes in protein levels [1,63,64,71–74], however, only three of these provide parallel data on mRNA and protein levels of both SERCA2 and phospholamban [1,63,64]. The major finding is the protein levels remain constant in cardiomyopathy despite of decreased mRNA levels. As an explanation for this apparently conflicting result, it is suggested that differential changes in synthesis and degradation of mRNA and proteins are associated with heart failure [1,63,64,75], so that determination of mRNA levels only is by no means representative of protein levels. On the other hand, measurements of protein concentration may be subject to larger variability leading to less reliable results than estimation of mRNA. This disparity may be even more exaggerated by small sample sizes due to the limited access to nonfailing control tissue. Furthermore, it may not suffice to characterize heart muscles merely as failing or nonfailing, because Hasenfuss et al. [69] could show that discriminating end-stage failing myocardium on the basis of diastolic function yielded two distinct subgroups, i.e., one with increased protein levels of Na⁺–Ca²⁺ exchanger but unchanged SERCA2 and another one with decreased protein level of SERCA2 but unchanged Na⁺–Ca²⁺ exchanger [69]. In addition, the relative phospholamban/SR Ca²⁺-ATPase ratio is critical in the regulation of myocardial contractility and alterations of this ratio may contribute to the functional deterioration observed during heart failure [76,77].

	6 Evidence for functional changes in SR Ca2+-handling proteins

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
Interpretation of the above biochemical findings is further complicated by plausible dissociations between protein concentration and function. Although there is general agreement in the literature that the protein levels of phospholamban are not altered in human failing myocardium, this does not necessarily imply that its function remains unaffected as well. Since phospholamban is phosphorylated by protein kinase A (or calcium/calmodulin-dependent protein kinase), any change leading to altered protein kinase activation will also indirectly affect regulation of the SR Ca²⁺ pump. As pointed out in the Introduction, heart failure may be compensated by sympathetic activation that leads to elevation of norepinephrine plasma concentrations causing further counter regulation at the receptor level. Thus in heart failure, the β-adrenoceptor signaling cascade, for instance, is functionally inactivated because selective downregulation of β₁-adrenoceptors [78] and upregulation of β-adrenoceptor kinase leads to uncoupling of the receptors [79]. Reduced protein kinase A activation impairs phosphorylation of phospholamban and consequently causes insufficient removal of the inhibitory action of unphosphorylated phospholamban. As a result, the function of the SR Ca²⁺ pump may become severely compromised.

Functional activity of the SR Ca²⁺-ATPase in failing and nonfailing myocardium can be examined by measuring Ca²⁺ uptake into SR vesicles and concomitant ATP consumption [80] or by studying systolic and diastolic [Ca²⁺]_i levels in intact cells under various Ca²⁺ loading conditions [15,69]. In different animal models of heart failure, vesicular Ca²⁺-ATPase activity is invariably depressed. These models include rats with ischemic cardiomyopathy [43,81], rabbits or dogs with tachycardia-induced heart failure [39–51,82] and guinea pigs with heart failure induced by aortic banding [52]. Incidentally in the latter study, impaired function was also associated with a decrease in protein levels of SR Ca²⁺-ATPase and phospholamban.

Corresponding decreases in SR Ca²⁺ uptake or SR Ca²⁺-ATPase activity are also observed in the failing human myocardium [63,64,67,73,74,83], however, other authors have not been able to show changes in pump activity [84,85]. Moreover, in the study of Schwinger et al. activities of SR Ca²⁺-ATPase as well as of Ca²⁺ uptake into the SR are decreased in the human myocardium despite unchanged protein expression [63].

Isolated heart muscle from most mammalian species responds to increasing frequency of stimulation with enhanced force development, but in failing myocardium from animals and human beings, the force–frequency response is blunted [16,68,69,86–91]. Hasenfuss et al. [69] explain this blunted response by impaired SR Ca²⁺ loading particularly with short stimulation intervals. In heart failure, shortening of the stimulation interval will unmask even subtle functional compromise of the SR Ca²⁺ pump because time may become too short for sufficient Ca²⁺ loading of the SR. In this group of muscles diastolic function is impaired during high frequency stimulation, which is explained by insufficient Ca²⁺ sequestration due to reduced SERCA2 levels. However, diastolic Ca²⁺ concentration should only be elevated transiently, because of other regulating processes, i.e., Na⁺–Ca²⁺ exchanger and, indirectly, also Na⁺–K⁺-ATPase. For long-lasting elevation of [Ca²⁺]_i these additional regulators would also have to be affected by heart failure. Interestingly, in some patients, cardiac expression of Na⁺–Ca²⁺ exchanger is upregulated during failure. Muscles from these hearts are found to be protected from diastolic dysfunction because cytosolic Ca²⁺ not taken up by the SR is removed from the cell due to enhanced exchanger activity [69].

	7 Other subcellular alterations in hearts failure

Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 
Heart failure is likely to induce multiple changes [92] and the time has come to take a fresh look at various key players of excitation–contraction coupling including L-type Ca²⁺ channels, ryanodine receptors, mitochondria, myofilaments. Recent evidence suggests that anyone of these structures may in fact be modified during heart failure despite the fact of earlier negative results [3,6,7,93,94]. In animal models, inconsistent changes of L-type Ca²⁺ currents in association with hypertrophy and failure have been reported [3]. However, our own findings of unchanged basic properties of L-type Ca²⁺ currents in human myocytes [94] have been confirmed [95,96], although frequency-induced upregulation [97] and β-adrenergic stimulation of this current [15] can be affected by failure. Abnormal coupling between the trigger (Ca²⁺ entry via L-type Ca²⁺ channels) and the release mechanism (Ca²⁺ flux through ryanodine-sensitive Ca²⁺ channels in the SR) appears to be an additional reason besides decreased Ca²⁺ loading of the SR for reduced [Ca²⁺]_i transients [94,98]. Impaired mitochondrial respiration has recently been shown to contribute to global cardiac dysfunction in the dog with chronic failure induced by microembolization [99].

The salient finding of prolonged relaxation time in the failing myocardium has been interpreted as impairment of Ca²⁺-handling proteins rather than changes in myofilament function [18]. These authors had been "surprised to find that isometric tension development in muscles from the failing hearts was not depressed significantly compared with the controls" [18]. However, delayed relaxation (or delayed [Ca²⁺]_i transients) can also be due to alterations at the level of the myofilaments [100] or myofibrillar calcium sensitivity [101]. In analogy to the action of so-called "Ca²⁺ sensitizers" that enhance the sensitivity of contractile proteins for Ca²⁺ binding but delay relaxation as a common side effect inherent in their mechanism of action [102], impaired dissociation of the Ca²⁺-myofilament complexes could contribute to slow relaxation in heart failure, although it should be noted that pure Ca²⁺ sensitizers are cardiotonic rather than cardiodepressive. Nevertheless, evidence for myofilament dysfunction in heart failure is slowly emerging [6,100,103]. Besides functional deficiencies, simple loss of contractile elements as anticipated from the recently recognized role of apoptosis in failure-induced remodeling may also contribute to contractile dysfunction [104–106].

Finally, in an attempt of rating the paper by Linck et al. [1] 3 years after its publication, we can state that this work — together with the paper by Schwinger et al. [63] published shortly before — have substantially contributed to our understanding of altered expression SERCA2 and phospholamban in heart failure. The controversy on whether or not changes at the level of mRNA are paralleled by alterations in protein level and function has attracted much attention from the scientific community, but should not divert research interests away from other possible cellular sites as targets for functional compromise.

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Top 1 Introduction 2 Cardiac excitation-contraction... 3 Summary of a... 4 SR calcium pump... 5 SR calcium pump... 6 Evidence for functional... 7 Other subcellular alterations... References

 

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