Cardiovascular Research

Cardiovascular Research 2001 49(1):1-6; doi:10.1016/S0008-6363(00)00284-4
© 2001 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

How can overexpression of Na⁺,Ca²⁺-exchanger compensate the negative inotropic effects of downregulated SERCA?

G. Isenberg^*

Department of Physiology, Martin-Luther-University, Halle, Germany

^* Tel.: +49-345-557-1886; fax: +49-345-557-4019 gerrit.isenberg{at}medizin.uni-halle.de

Received 1 November 2000; accepted 1 November 2000

See article by Terracciano et al. [2] (pages 38–47) in this issue.

	1 Importance of the Na+/Ca2+-exchanger for the Ca2+ distribution in the failing human heart

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
The failing human ventricle suffers from two major problems: (1) During diastole, relaxation is retarded and remains eventually incomplete. (2) During systole, the force-frequency relation is blunted, i.e. an increase from 60 to 120 beats-per-min does not increase the contractile force as it is typical in non-failing tissue. Both problems have been linked to reduced expression and function of sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA) proteins. Studies in isolated human ventricular trabeculae [1] have shown that incomplete Ca²⁺ reuptake by SERCA can cause (1) a diastolic accumulation of Ca²⁺ ions in the cytosol which impairs diastolic relaxation, and (2) a reduction of releasable SR Ca²⁺ with the consequence of a reduced systolic Ca²⁺ activation of force and a blunted force-frequency relation. Since failing human myocardium was shown to overexpress the Na⁺/Ca²⁺-exchanger (mRNA and protein [1]), enhanced Ca²⁺ efflux by Na⁺/Ca²⁺-exchange has been suggested to partially compensate impaired diastolic Ca²⁺ removal. The paper of Terracciano et al. ([2] in this issue) confirms this view. In addition, it introduces a new idea: the enhanced expression and function of the Na⁺/Ca²⁺-exchanger may facilitate Ca²⁺ reuptake by SERCA and thereby compensate for the impaired SR Ca²⁺ load.

	2 Transgenic mice with overexpressed Na+/Ca2+-exchanger as a model

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Terraciano et al. [2,3] compared protein concentrations and functions between ventricular myocytes from transgenic mice (TR) that overexpress the Na⁺/Ca²⁺-exchanger and non-transgenic (non-TR) wild-type littermates. They find that the protein levels of the Na⁺/Ca²⁺-exchanger are approximately 2.4-fold elevated [3,4]) whilst the concentrations of other Ca²⁺ handling proteins such as SERCA, calsequestrin and phospholambam were not different. With this background, the authors can evaluate the consequences of the overexpression of a single protein species for the Ca²⁺ fluxes mediated by Na⁺/Ca²⁺-exchange.

	3 The balance of Ca2+ fluxes

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Tearraciano et al. [2] evaluated the Ca²⁺ fluxes from experiments that measured time-dependent changes (d/dt) of the concentration of Ca²⁺ ionized in the cytosol ([Ca²⁺]_c) by means of the fluorescence indicator Indo-1. There are several fluxes that increase and decrease [Ca²⁺]_c during the contractile cycle (from [5]):

(1)

The SR Ca²⁺ release flux (J_rel) contributes most (ca. 80%) of the Ca²⁺ when the transient rises to its peak, it is complemented by Ca²⁺ influx through L-type channels (I_Ca,L) and via Na⁺/Ca²⁺-exchange operating in Ca²⁺ influx mode (J_x,inf). [Ca²⁺]_c is decreased (negative sign) by SR Ca²⁺ re-uptake (J_SERCA) and by Ca²⁺ efflux via Na⁺/Ca²⁺-exchange (J_x,eff). Last not least, ionized Ca²⁺ binds to (–J_lig) and unbinds from (+J_Lig) numerous ligands such as troponin C. When the cellular Ca²⁺ load is steady, i.e. when the frequency is constant and no pharmacological interventions are done, the sum of the positive and negative fluxes has to be in balance.

	4 Na+/Ca2+-exchange provides both Ca2+ efflux and Ca2+ influx

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Our conventional understanding of how the Na⁺/Ca²⁺-exchanger contributes to the Ca²⁺ transient is dominated by the interpretation of the positive inotropy caused by cardioactive glycosides [6]. According to the "Na⁺-lag hypothesis" [7] ouabain inhibits the Na⁺/K⁺-ATPase, the increase in the cytosolic sodium concentration [Na⁺]_c reduces J_x,eff, and a correspondingly larger part of Ca²⁺ ions is sequestered by J_SERCA. Amplitude and direction of Ca²⁺ flux via Na⁺/Ca²⁺-exchange are determined by the difference (V_m–E_x). V_m is the membrane potential, and for the reversal potential for the exchanger one can write (e.g. [5])

(2)

At start of the action potential (AP), [Ca²⁺]_c is low, E_x is with approximately –26 mV [3] negative to V_m (+30 mV), and the Na⁺/Ca²⁺-exchanger operates in the Ca²⁺ influx mode. When the Ca²⁺ transient peaks, E_x increases beyond V_m and the exchanger changes into the Ca²⁺ efflux mode (J_x,eff, positive in Fig. 2). During the following time, direction and amplitude of the Ca²⁺ flux depend on both fall of [Ca²⁺]_c (more negative E_x) and AP repolarization (V_m), usually the amplitude fades away but the direction does remains in the Ca²⁺ efflux mode (Fig. 2). Increments in [Na⁺]_c e.g. due to ouabain shift E_x to more negative potentials, and the reduced driving force attenuates J_x,eff with the result that more Ca²⁺ is sequestered by J_SERCA (compare [8]).

View larger version (33K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Modelled Ca2+ flux via Na+/Ca2+-exchange in dependence on [Ca2+]c, [Na+]c and membrane potential Vm. The calculations used the equation from Kimura et al. [14] Ix=const*{([Na+]c3*[Ca2+]c* exp(0.5/β*Vm)–[Na+]o3*[Ca2+]c* exp(–0.5/β*Vm)}. β = RT/F is 39 mV, [Na+]c is 9.6 mM [3]. Vm (light grey, right ordinate) and [Ca2+]c (dark line, left ordinate) are data from Fig. 1. Traces at the top: non-calibrated Ix, Ca2+ influx positive. Note: this model does not incorporate effect of Ix on other Ca2+ fluxes or on SR Ca2+ loading. A: Ca2+ transients due to 80 ms clamp steps, data from Fig. 1. After a spiky Ca2+ influx, the Na+/Ca2+-exchanger operates in Ca2+ efflux. The dotted line (top) suggest that cellular Ca2+ load would progressively fall when ICa,L were absent. B: Action potential (AP) induced Ca2+ transients (bottom) are fast and of large amplitude (own unpublished experiments). AP repolarization at high [Ca2+]c induces large Ca2+ efflux that decays with diastolic fall of [Ca2+]c to a steady value. Cellular Ca2+ load would fall (dotted line). C: In the small volume of the fuzzy space [Ca2+]SL (dotted line) could fall faster and to lower concentrations than global [Ca2+]c (solid line), turning Na+/Ca2+-exchange into Ca2+ influx mode. Diastolic Ca2+ influx, however, is based on the unlikely assumption that [Ca2+]SL would stay below [Ca2+]c. D: Long APs keep Vm positive to Ex thereby promoting Ca2+ influx and cellular Ca2+ load.

 

	5 The Ca2+ transients in myocytes from transgenic mice

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Terracciano et al. compare the Ca²⁺ transients between field-stimulated TR and non-TR myocytes. The results suggest (see Fig. 1 in [2]):

1. The Ca²⁺ transients peak earlier (time to peak, TTP, 100 instead of 146 ms) and last shorter in TR than in non-TR myocytes (234 instead of 332 ms for TTP+T50=time to 50% decay). The faster time course is expected in a cell where J_x,eff is enhanced whilst the other Ca²⁺ fluxes are non-modified.

2. The amplitude of the Ca²⁺ transients is not significantly different between TR (126 nM) and non-TR myocytes (133 nM). Result (2) is somewhat unexpected; augmented J_x,eff (overexpression) should have reduced the peak Ca²⁺ by earlier cutting off its rising phase (the Ca²⁺ transient peaks when I_Ca+J_rel+J_x,inf=J_SERCA+J_x,eff). By competition with J_SERCA, augmented J_x,eff should have diminished the SR Ca²⁺ load, as a consequence a smaller J_rel should have caused a smaller peak [Ca²⁺]_c.

3. The Ca²⁺ transients of TR and non-TR myocytes superimpose after TTP and TTP+T50 of TR myocytes has been prolonged by inhibiting J_SERCA of TR myocytes by 200 µM thapsigargin.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Ca2+ transients of isolated mouse ventricular myocytes. Cell was loaded with 50 µM K5Indo-1 via patch pipette, voltage clamped at 4 Hz and superfused with a 37°C warm physiological salt solution containing 2 mM [Ca2+]o. Top: membrane currents in response to 80 ms pulses from –45 to +5 mV. Bottom: [Ca2+]c calculated from the ratiometric measurements. After a delay of 10 ms, [Ca2+]c peaks within 36 ms to 1180 nM (dot). From the peak, [Ca2+]c falls along an exponential time course to a diastolic concentration of 110 nM (solid line shows fit with single time constant of 140 ms).

 

	6 In myocytes from transgenic mice, SR Ca2+ load is augmented

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
As an explanation for the constant amplitude of the Ca transient in TR and non-TR myocytes, Terraciano et al. [2] suggest that overexpression of Na⁺,Ca²⁺-exchanger facilitates the SR Ca²⁺ load. The idea was tested by experiments in Ca²⁺- and Na⁺-free extracellular solution where the Na⁺/Ca²⁺-exchanger does not operate. With J_x,eff=0, the decay of the Ca²⁺ transient can quantify J_SERCA. The amplitudes of the caffeine induced Ca²⁺ transients were 1556 nM in TR and 880 nM in non-TR myocytes, suggesting that the TR had a larger SR Ca²⁺ content than non-TR myocytes. J_SERCA and J_x,eff cannot be directly extracted from the Ca²⁺ transient (since the decay rate depends also on J_Lig that varies with [Ca²⁺]_c [9]). Instead, the authors estimate J_SERCA and J_x,effl and plot them as a function of pCa. Their fit with sigmoidal functions yields the following flux parameter: in non-TR myocytes, SERCA operates with a K_m of 0.4 µM and a V_max of 99 µM/s, the Na⁺,Ca²⁺-exchanger with a K_m 0.4 µM and a V_max of 21 µM/s. In TR myocytes J_SERCA has identical values, however, the Na⁺/Ca²⁺-exchange shows a more than doubled V_max=53 µM/s at unchanged K_m=0.4 µM.

In an independent set of voltage-clamp experiments [2], the authors measure the flux of releasable SR Ca²⁺ (J_rel) as current J_x,eff (influx of 3 Na⁺ ions in exchange of 1 Ca²⁺ ion). Following the suggestions of the Eisner Laboratory [10], J_rel was activated by rapid application of 10 mM caffeine for 12 s. In continuous presence of caffeine, the SR release channels do not close and J_SERCA is ineffective, hence, all released Ca²⁺ ions are extruded via J_x,eff. The authors estimate from the rates that the flux J_x,eff is 1.7-fold larger in TR than in non-TR myocytes. The time integral of the caffeine-induced inward current I_x,eff reflects the amount of the caffeine-releasable SR Ca²⁺ [9]. The authors estimate that the SR of TR is loaded with significantly (32%) more Ca²⁺ than the SR of non-TR myocytes, and that this difference disappears after SERCA inhibition by thapsigargin.

	7 Problems in quantification of the Ca2+ flux

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Different to the caffeine-induced Ca²⁺ transients, Ca²⁺ transients induced by action potentials (field stimulation) were of low amplitude (approximately 130 nM, Fig. 1 [2]). The low amplitude and the long duration (234 and 332 ms, in non-TR and TR myocytes, respectively) of the Ca²⁺ transients are in conflict with the duration of contraction that was 128 (TR) and 164 ms (non-TR) as well as with the literature on Ca²⁺ transients where the myocytes were loaded with the acid form of Indo-1 instead of the acetoxy methylester (AM). An example for isolated mice ventricular myocytes is shown in Fig. 1: [Ca²⁺]_c starts from diastolic 100 nM, rises after a 10 ms delay, peaks to 1100 nM 36 ms after start of the clamp step, and completely relaxes within 200 ms. Thus, the 4 Hz stimulation does not induce a diastolic Ca²⁺ accumulation or incomplete relaxation. Similar fast and large Ca²⁺ transients have been measured from mouse trabeculae loaded with the acid form of Indo-1 [11] We interpret that the low amplitude and the slow kinetics of the Ca²⁺ transients in Fig. 1 [2] were caused by Indo-1 that has been loaded as AM into mitochondria, i.e. that the superimposition of the slow changes of mitochondrial [Ca²⁺] upon the fast cytosolic signals could result in records like those in Fig. 1 [2].

Presumably, the exchange of Ca²⁺ between cytosol and mitochondria is fast enough to equilibrate within the 12 s between the subsequent caffeine applications. However, mitochondrial Ca²⁺ uptake can also modulate the decay rate of the caffeine-induced Ca²⁺ transients, hence the quantification of the Ca²⁺ fluxes is considered with some skepticism. Together with Terraciano et al., I would like to assume that the loading indo-1-AM into compartments is similar in TR and non-TR cells. Also, one would have to postulate that the cytosolic buffering power for Ca²⁺ is the same in the two sorts of cells (see J_lig in Eq. (1)). The authors discuss these problems and hope to resolve them in future. Although some skepticism in regard to the quantification of the fluxes is left, the comparison between the Ca²⁺ signals in TR and non-TR myocytes on the base of relative numbers should be valid.

	8 Mechanisms by which overexpressed Na+/Ca2+-exchanger could augment SR Ca2+ filling

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
How can a Ca²⁺ efflux increase the SR Ca²⁺ load by 30% when it operates at a faster rate in TR than in non-TR myocytes?

8.1 Faster decay of [Ca²⁺]_c
The authors have shown that augmented J_x,eff can speed up the time course of the Ca²⁺ transients. They argue that the faster decay of [Ca²⁺]_c would shift E_x earlier in time to the positive values at which Na⁺,Ca²⁺-exchange would operate as J_x,inf, feeding J_SERCA and thereby Ca²⁺ loading the SR [2,3]. Teracciano et al. [3] had measured that the reversal potential E_x was not different in TR and non-TR myocytes, [Na⁺]_c was 9.6 and 9.6 mM, [Ca²⁺]_c 159 and 135 nM and E_x –27 was and –24 mV, respectively, and model calculations suggest that the Na⁺/Ca²⁺-exchanger would operate in Ca²⁺ efflux nearly all time (see Fig. 2A and B). To solve this dilemma, one may assume that E_x is not controlled by the global concentration [Ca²⁺]_c (measured by the photomultiplier from the whole cell) but by the local concentrations [3] in the approximately 15 nm narrow subsarcolemmal space (index SL, synonymous "fuzzy space" [12,13]). In this very small volume, augmented J_x,eff could reduce [Ca²⁺]_SL at a rate faster and to concentrations lower than those indicated by [Ca²⁺]_c. If [Ca²⁺]_SL would be as low as e.g. 60 nM, the Na⁺,Ca²⁺-exchanger would operate in Ca²⁺ influx mode most of the time (Fig. 2C). However, in order to reduce [Ca²⁺]_SL below [Ca²⁺]_c, there must be a net Ca²⁺ efflux from the cell, i.e. the Na⁺,Ca²⁺-exchanger must operate in Ca²⁺ efflux mode and could not operate as J_x,inf feeding J_SR. Thus, without an additional Ca²⁺ efflux mechanism (plasmalemmal Ca²⁺ ATPase?) the above explanation seems to be unlikely.

8.2 Faster accumulation of [Na⁺]_SL
J_x,eff should increase [Na⁺]_SL along a time course that is faster in TR than in non-TR myocytes, and E_x could reach potentials where Na⁺/Ca²⁺-exchange would run as J_x,inf at earlier times. However, the effect should be transient since J_x,inf (and Na⁺,K⁺ATPase operating in parallel) would restore [Na⁺]_SL more rapidly in TR than in non-TR myocytes. As discussed above for Ca²⁺ accumulation, faster Na⁺ accumulation could change the time course of the decay in activator Ca²⁺. To net cellular Ca²⁺ load, however, [Na⁺]_c should accumulate independent of the Na⁺/Ca²⁺-exchanger, for example due to inhibition of the Na⁺,K⁺ATPase with ouabain [8].

8.3 Longer action potential (AP)
The inward current generated by Ca²⁺ influx prolongs the plateau of the AP. Even at low [Ca²⁺]_c, the Na⁺/Ca²⁺-exchanger can operate in the Ca²⁺ influx mode when the membrane potential is positive to E_x (see Fig. 2D). Unfortunately, the authors do not provide information whether the AP in TR is longer than non-TR myocytes.

In summary, we are still waiting for the definite answer which mechanism is facilitating the filling of the SR Ca²⁺ stores in TR myocytes with increased activity of Na⁺,Ca²⁺-exchange.

	9 The overexpressed Na+/Ca2+-exchanger can compensate for suppressed SERCA activity

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
In TR cells (elevated J_x), inhibition of J_SERCA with thapsigargin prolongs the duration of the Ca²⁺ transient and the duration of the twitch. The authors plot these values as a function of exposure time to thapsigargin and compare them with those from non-TR myocytes (no thapsigargin). The comparison indicates that Ca²⁺ transients and twitches in TR myocytes (2.4-fold increased Na⁺,Ca²⁺-exchange activity) correspond to those from non-TR controls when SERCA activity is inhibited by 28%. The authors extrapolate to the failing heart: a 28% reduced SERCA function can be compensated by a 2.4-fold increase in Na⁺/Ca²⁺-exchange activity.

	10 From the transgenic mice back to the failing human heart

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
Human heart failure has been classified in three groups of increased severity [1]. When compared with non-failing hearts, the reduction of SERCA protein was significant in group III (48% reduction) but not in groups II or I (42 and 27% reduction). Na⁺/Ca²⁺-exchanger protein was unchanged in group III but increased by 80% in group I, this overexpression correlated inversely with the impaired diastolic relaxation [1]. Speculating that reduction of SERCA in failing human hearts of group I could become significant when more data could have been analyzed, the interpretation of the group I failure in human hearts would be in analogy to the first conclusion of Terraciano et al. [2], i.e. the increase in Na⁺/Ca²⁺-exchange activity (2.4-fold) can compensate the disturbed Ca²⁺ redistribution caused by a modest (28%) inhibition SERCA.

The second major conclusion of Terraciano et al. [2] was that the increased activity of Na⁺,Ca²⁺-exchange increases via J_x,inf the SR Ca²⁺ load and thereby the amount activator Ca²⁺. I am not yet ready to accept this conclusion in general terms, or to extrapolate it to the failing human heart. For example, the amplitudes of the physiological systolic Ca²⁺ transients of TR, TR thapsigargin-treated and non-TR myocytes were not significantly different (Fig. 1 [2]). Further, experiments on trabeculae from failing human hearts indicated a reduced SR Ca²⁺ load, as if the overexpressed Na⁺/Ca²⁺-exchanger had increased the activity of J_x,eff and not of J_x,inf [1]. Obviously, quantification of J_SERCA, J_x,inf and J_x,eff from Ca²⁺ transients in mice or human preparations is a difficult task that needs knowledge not only of [Ca²⁺]_c but also of the cytosolic Ca²⁺ buffering power, the volume fraction of the SR etc., numbers whose extrapolation from rat ventricular myocytes is questionable. In addition to the changed expression of SERCA and Na⁺,Ca²⁺-exchanger proteins, additional influences such as cell hypertrophy, metabolism etc. are likely to be involved in development of cardiac failure. In the transgenic mouse model, Terraciano et al. [2–4] have analysed the isolated effects of two key proteins, and obtained results that are necessary and important for the further understanding of the complex interactions during development of cardiac failure.

	Acknowledgments

Top 1 Importance of the... 2 Transgenic mice with... 3 The balance of... 4 Na+/Ca2+-exchange provides... 5 The Ca2+ transients... 6 In myocytes from... 7 Problems in quantification... 8 Mechanisms by which... 9 The overexpressed Na+/Ca2+... 10 From the transgenic... Acknowledgments References

 
I thank J. Borschke for experimental support and Drs. D. Eisner and J. Holtz for critical discussions.

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