Cardiovascular Research

Cardiovascular Research 1998 37(2):346-351; doi:10.1016/S0008-6363(97)00260-5
© 1998 by European Society of Cardiology

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Copyright © 1998, European Society of Cardiology

Sarcoplasmic reticulum in heart failure: central player or bystander?

Ronald M Phillips^a,1, Prakash Narayan^a,2, Ana M Gómez^b, Keith Dilly^b, Larry R Jones^c, W.Jonathan Lederer^b and Ruth A Altschuld^a,*

^aDepartment of Medical Biochemistry, Ohio State University Medical Center, 333 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA
^bDepartments of Molecular Biology and Biophysics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
^cKrannert Institute of Cardiology and Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

^* Corresponding author. Tel. (+1-614) 292 1158; Fax (+1-614) 292 4118; E-mail: altschuld.2@osu.edu

Received 9 September 1997; accepted 17 October 1997

	1 Introduction

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Myocardial excitation-contraction coupling begins with membrane depolarization, a process that activates voltage-sensitive Ca²⁺ channels in the sarcolemma and allows a small amount of Ca²⁺ to enter the cell. This Ca²⁺ serves as a trigger to activate Ca²⁺-release channels in the adjacent junctional sarcoplasmic reticulum (SR) [1]: the ensuing efflux of stored SR Ca²⁺ increases the cytosolic free Ca²⁺ ion concentration ([Ca²⁺]_i) and initiates contraction. The amount of Ca²⁺ released by the SR depends on the size of its Ca²⁺ load and on the size and duration of the initial Ca²⁺ trigger. This allows [Ca²⁺]_i transient amplitudes to be graded [2]— an important feature in cardiac muscle, where all cells contract with each beat. Modulation of the [Ca²⁺]_i transient amplitude provides one mechanism to vary the force of contraction and thereby match cardiac output to the body's metabolic demands.

Myocardial relaxation occurs when Ca²⁺ is removed from the cytosol, and re-uptake by the SR is quantitatively the most important mechanism for decreasing cytosolic [Ca²⁺]_i. This is accomplished through the activity of the SR Ca²⁺ pump protein, SERCA2, a Ca²⁺-activated ATPase that pumps Ca²⁺ into the SR lumen. Re-uptake occurs in the non-junctional SR, primarily in the SR membrane and Ca²⁺ ATPase rich portion of the cell near the transverse tubules, at the Z-line of the sarcomere [3].

Activity of the cardiac SR Ca pump is tonically inhibited by an endogenous SR component, phospholamban [4]. Phospholamban is a low molecular weight protein that can exist as either a pentamer or a monomer. Each phospholamban monomer contains two amino acid residues that can be phosphorylated by protein kinases in vivo: a serine 16 that is phosphorylated by protein kinase A and a threonine 17 that is phosphorylated by a Ca²⁺/calmodulin-dependent protein kinase [5]. Phosphorylation of phospholamban relieves the inhibition of SERCA2, and part of the positive inotropic effect of β-adrenergic stimulation is due to the protein kinase A-dependent phosphorylation of serine 16, an effect potentiated by the concomitant Ca²⁺/calmodulin-dependent phosphorylation of threonine 17. This accelerates SR Ca²⁺ accumulation and increases the amount of Ca²⁺ available for release in subsequent heartbeats.

Accumulated SR Ca is bound to a low affinity, high capacity protein termed calsequestrin [6]. This protein, like the SR Ca²⁺ release channel protein, is confined to regions in the SR that store and release Ca²⁺, that is the junctional regions closely associated with the t-tubules and the non-junctional ‘corbular’ SR.

	2 SR function in heart failure

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Aspects of myocardial contraction and relaxation associated with Ca²⁺ uptake and release by the SR are altered in the failing heart [7]. More than a century ago, Traube noted that patients with severe congestive heart failure tend to have alternating strong and weak pulses, or pulsus alternans [8]. This now widely recognized hallmark of congestive heart failure is caused by an alternation of weak and strong myocardial contractions termed mechanical alternans. Mechanical alternans, in turn, is caused by an alternation in the amount of SR Ca²⁺ release [9]. There can also be an accompanying electrical alternans (alternating short and long action potentials) in heart failure, but this appears to be a secondary response to alternating [Ca²⁺]_i transient amplitudes [10]. In isolated ventricular muscle, alternans can be readily abolished by agents such as caffeine and ryanodine that activate SR Ca²⁺ release [11].

Other features of SR Ca²⁺ cycling are also abnormal in the failing heart. There is a flattened force-frequency relationship, instead of the positive treppe characteristic of cardiac muscle from healthy larger mammals [18, 19]. Failing myocardium may also have blunted and/or prolonged [Ca²⁺]_i transients [12, 13]. Finally, mechanical restitution, a process whereby cardiac muscle regains its ability to contract following a stimulus, is delayed in heart failure [14].

Alterations in [Ca²⁺]_i -dependent phenomena in failing cardiac muscle have been widely assumed to result, at least in part, from a slowed rate of Ca²⁺ uptake by the SR. Indeed, mechanical alternans can be induced in normal myocardium by acidosis, lowered extracellular Ca²⁺, hypothermia, or ischemia [15–17]— all of which are well known to retard the rate of SR Ca²⁺ uptake. However, a sluggish SR Ca²⁺ pump may not be the entire answer to altered Ca²⁺ handling. Although one can simulate the flattened force-frequency relationship of heart failure [18, 19]by inhibiting SERCA2 [20], such inhibition does not provoke alternans in normal cardiac muscle [11]. Moreover, as will be described below, there is disagreement on the status of SERCA2 in failing hearts.

	3 SERCA2 and SR Ca2+ uptake in failing hearts

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
In most [21–30]but not all [31]studies of failing ventricular muscle, SERCA2 mRNA has been depressed. The situation with respect to the amount of SERCA2 protein is less clear, however. There have been reports of decreased SERCA2 in some failing rat [21, 24, 25]and human [18, 32–34]hearts, but not in others [27–29, 35]. Finally, in a study where both mRNA and protein were measured, the fractional decline in SERCA2 mRNA was more than double the decline in SERCA2 protein [36].

With regard to SERCA2 function, SR Ca²⁺ uptake can be depressed [21, 29, 34, 37, 38]or unaltered [39, 40]in hypertrophied and/or failing myocardium. It should be noted, however, that few studies have assessed the status of phospholamban phosphorylation in these preparations. Differences in the degree of phospholamban phosphorylation between normal and failing hearts could strongly influence the results, and phospholamban phosphorylation has been shown to occur in vitro in the absence of β-adrenergic agonists [41].

	4 The SR Ca2+ release channel, or ryanodine receptor, in failing hearts

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
The SR Ca²⁺ release channel, often referred to as the ryanodine receptor (RyR) because of its affinity for the plant alkaloid, ryanodine, is a homotetramer composed of 564 kDa subunits [42]. This large protein forms the ‘foot structures’ seen in electron micrographs of cardiac dyads [43]. There are indications that RyR function may be altered in heart failure, but the extent to which this is due to altered gene expression is unclear. In myocytes from failing hypertensive SHHF/Mcc-fa^cp rats, however, the distribution of ryanodine receptors is unchanged relative to that seen in normal rat cells (Fig. 1), despite the clear alterations of excitation-contraction coupling previously observed in this model [11, 58].

View larger version (64K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Ryanodine receptor distribution in control (top) and failing (bottom) rat heart cells. Age-matched Sprague-Dawley rats (18 months old) normal heart cells are compared with SHHF/Mcc-facp rat heart cells in overt clinical heart failure [58]. Cells were fixed and permeabilized using 100% ethanol (15 min at –20°C), rinsed with 5% normal goat serum (NGS) and 3% bovine serum albumin (BSA) in phosphate buffered saline (PBS) and incubated with monoclonal primary antibodies (1:50 dilution overnight on a rocking platform at 5°C) against RyR. Cells were then rinsed 4 times with NGS/BSA in PBS, after which secondary antibodies were added (1:200) for 2 h at room temperature. Goat anti-mouse IgG (GAM) conjugated to fluorescene was used to label monoclonal primary antibodies. Cells were viewed using laser scanning confocal microscopy. Confocal microscopy was carried out on cells using a Zeiss 410 system microscope using excitation light of 488 nm and measuring emissions at 515–565 nm. The enlargement inset in each image clearly shows the distribution of the RyR which has been shown to be enriched along the z-lines of the SR.

 
A decreased density of RyRs has been observed in a rat model of pressure overload hypertrophy [44], but failing human hearts have contained normal levels of RyR protein [18, 32, 33]. The data regarding mRNA levels in failing human hearts are somewhat contradictory, and seem to depend on etiology. In dilated cardiomyopathy, both decreases [45]and no change [46]in mRNA levels have been observed. In ischemic cardiomyopathy, there are decreased levels of mRNA [45, 46], but again, there are no changes in RyR protein levels [32].

	5 Calsequestrin in failing hearts

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
The calsequestrin content of the heart does not seem to be altered in heart failure. Studies of both mRNA [30, 47]and protein [18, 32, 33, 35]have shown no differences between failing and non-failing human hearts. For this reason, the relative amounts of other SR proteins are often normalized to calsequestrin, especially when there are concerns about variable amounts of non-myocyte protein in various tissue samples. Interestingly, although calsequestrin content is unchanged in most failing hearts, transgenic mice overexpressing cardiac calsequestrin 18-fold have pronounced cardiac hypertrophy and congestive heart failure accompanied by abnormalities in Ca²⁺-induced Ca²⁺ release from the SR [48].

	6 Phospholamban in failing hearts

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Phospholamban mRNA levels have been unchanged in failing rat hearts [26]and decreased in human heart failure [27–30, 49]. Phospholamban protein levels have been found to be decreased in some studies of human failure [18, 33]and unchanged in others [27–29, 35, 50]. A decrease in phospholamban could be viewed as a compensatory change that would relieve inhibition of SERCA2 in failing hearts, which typically have a blunted response to β-adrenergic stimulation [51]. On the other hand, one would predict that the ability to modulate cardiac output would be impaired.

	7 Local control and excitation-contraction uncoupling in heart failure

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Until quite recently, models of cardiac excitation-contraction coupling assumed that Ca²⁺ influx across the sarcolemma through the voltage-gated L-type Ca²⁺ channels increases the [Ca²⁺]_i concentration of a common cytosolic pool. This slight [Ca²⁺]_i increase was thought then to trigger Ca²⁺ release from the SR. However, there were problems with this common pool model [2, 52], Ca²⁺ released from one portion of the SR, for example, does not trigger the release of Ca²⁺ from distant junctional SR pools [53]. That is, Ca²⁺-induced SR Ca²⁺ release is not regenerative. This has led to the hypothesis that Ca²⁺-induced SR Ca²⁺ release is under local control [54].

The discovery of ‘Ca²⁺ sparks’ has given considerable support to the local control theory [55, 65]. Using laser scanning confocal microscopy of fluo-3 loaded isolated myocytes, Lederer and colleagues detected single stochastic Ca²⁺ release events, approximately 20 ms in duration, arising from single or small clusters of RyRs [55]. In non-stimulated myocytes, these Ca²⁺ sparks did not propagate unless the SR was overloaded with Ca²⁺, in which case the frequency of spark production increased substantially. This occasionally allowed adjacent simultaneous sparks to coalesce and trigger waves of SR Ca²⁺ release and myofibrillar shortening [56].

In response to membrane depolarization, the frequency of spark production increases as a function of sarcolemmal Ca²⁺ current, and summation of the Ca²⁺ sparks gives rise to a typical whole cell Ca²⁺ transient [55, 57]. In hypertrophied and failing myocytes, the relation between trigger Ca²⁺ and spark frequency is altered such that more L-type Ca²⁺ current is needed to produce a given number of Ca²⁺ sparks [58]. That is, there is a degree of excitation-contraction uncoupling in heart failure.

	8 Frequency-dependent phenomena in failing hearts

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Another assumption about cardiac excitation-contraction coupling had been that frequency-dependent changes in contractile force reflect, in part, the time needed for Ca²⁺ taken up by the longitudinal SR to travel to the junctional and corbular sites of Ca²⁺ release. By extension, the altered frequency-dependent behavior of failing hearts was attributed to impaired SR Ca²⁺ uptake and an even slower filling of the SR release sites. However, studies of SR Ca²⁺ content using electron probe microanalysis [59]and of free [Ca²⁺] using [60]have shown that SR refilling is too rapid to explain attenuated extrasystolic beats or alternans. It has also been shown with caffeine pulses and rapid cooling contractures that the SR releases only a fraction of its available Ca²⁺ with each beat [61]. This led to the concept that the RyRs enter a refractory period after Ca²⁺ release. However, studies of individual SR Ca²⁺ release channels incorporated into planar lipid bilayers have failed to detect a true refractory state. Instead, there is a process termed adaptation, where sensitivity to a given level of activator Ca²⁺ declines as a function of time but where a further increase in [Ca²⁺] can trigger an increase in the probability of channel opening [62–64]. It may be that RyRs in vivo can exhibit both adaptation and a refractory state.

	9 Is the SR a central player or a bystander in heart failure?

Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 
Altered Ca²⁺ uptake and release by the SR accounts for many of the abnormalities in excitation-contraction coupling seen in the failing myocardium. However, these abnormalities probably do not arise primarily from an altered amount of individual SR proteins. As shown in this review, SERCA2, phospholamban, and the RyR can be present in normal amounts in hearts with end stage failure. In some instances, SR Ca²⁺ uptake can also be normal.

The alternative explanation for altered SR function in heart failure is that the interaction between the L-type Ca²⁺ channels of the sarcolemma and the Ca²⁺ release channels of the SR is altered, possibly through a subtle change in the spatial organization of the dyad (see Gómez et al., this issue). Regulation of the gating of the RyRs may also differ in the failing myocyte. For example, isoproterenol is able to normalize the relation between L-type Ca²⁺ channel current and spark production in cells from rats with compensatory hypertrophy, but not in those from hearts with end stage failure [58]. More research is needed to characterize, in detail, the regulation of SR Ca²⁺ release in the normal and failing heart.

In summary, the SR is clearly a central player and not a bystander in heart failure. However, changes in SR function are highly complex and do not necessarily involve changes in the amount of various SR components.

Time for primary review 10 days.

	Acknowledgements

 
We thank the Bennett Society, the Spanish Ministry of Education and Science, the Maryland Heart Association, the NIH for support of this work.

	Notes

 
¹ Present address: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.

² Present address: Dept. of Surgery, University of Kentucky Medical Center, Lexington, KY 40536, USA.

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Top 1 Introduction 2 SR function in... 3 SERCA2 and SR... 4 The SR Ca2+... 5 Calsequestrin in failing... 6 Phospholamban in failing... 7 Local control and... 8 Frequency-dependent phenomena... 9 Is the SR... References

 

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