© 2000 American Heart Association, Inc.
Editorial |
Na+-Ca2+ Exchange in Failing Myocardium
Friend or Foe?
From the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah.
Correspondence to William H. Barry, MD, University of Utah Health Sciences Center, Division of Cardiology, 50 North Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu
Key Words: myocardium • Na+-Ca2+ exchange • sarcoplasmic reticulum
 |
Introduction |
|---|
 Top Introduction References |
|---|
The Na+-Ca2+ exchanger (NCX) is a cation transporting protein present in the plasma membrane of animal cells. NCX transports three Na+ in exchange for one Ca2+ and thus is electrogenic; the function of the exchanger is controlled by the gradients for Na+ and Ca2+ across the cell membrane and membrane potential.1 In normal cardiac myocytes, NCX plays an important role in Ca2+ homeostasis. NCX functions in a forward mode, in which Na+ enters the cell and Ca2+ is extruded. The rate of Ca2+ extrusion by NCX is much greater than by the sarcolemmal Ca2+ pump,2 and Bridge et al3 have shown that NCX extrudes the amount of Ca2+ that enters the cell via the L-type Ca2+ channel as Ca2+ current, thus maintaining Ca2+ homeostasis on a beat-to-beat basis. As NCX extrudes Ca2+ and thus lowers Ca2+ from its peak, it contributes to relaxation in parallel with Ca2+ uptake by the sarcoplasmic reticulum (SR) Ca2+-ATPase.4 The extent to which NCX contributes to the decline of the Ca2+ transient varies between species,5 because the relative balance between the activities of these two Ca2+ removal systems is influenced by their level of expression, the [Na+]i, and the duration of the action potential. In rats and mice, which have a high level of activity of the SR Ca2+-ATPase and a relatively high [Na+]i, NCX is responsible for only
10% of relaxation. In rabbits, which have a
lower [Na+]i and SR
Ca2+-ATPase activity, NCX contributes more
significantly to the decline of the Ca2+
transient, especially during the terminal phase of the
transient.6 NCX can also produce Ca2+ influx by operating in the reverse mode. Electrochemical considerations indicate that early after the upstroke of the action potential, before a rise in intracellular [Ca2+]i occurs because of Ca2+-induced Ca2+ release, Ca2+ influx on the exchanger will occur.7 Ca2+ influx can also occur after decline of the [Ca2+]i transient if the duration of the action potential is long. The magnitude of this influx is dependent on the magnitude and rate of rise of the [Ca2+]i transient, the density of NCX in the sarcolemmal membrane, and the [Na+] adjacent to NCX in the subsarcolemmal space, which is influenced by the Na+ pump activity and INa as well as by the bulk cytosolic [Na+].8 The functional importance of reverse-mode NCX (Ca2+ influx) has been debated. This mode of NCX function has been proposed to increase the content of Ca2+ in SR,9 10 11 modulate the effectiveness of the L-type Ca2+ channel current in inducing Ca2+ release,12 13 14 and directly induce Ca2+ release,15 16 17 18 although other experimental work does not support a significant role for NCX-induced Ca2+ release in excitation-contraction (EC) coupling.19 20
Recent work in which NCX activity has been increased or decreased in isolated myocytes has provided conflicting data regarding the physiological importance of Ca2+ influx via NCX. Studies in transgenic murine myocytes that overexpress the exchanger by 2.5-fold have indicated that rather than producing Ca2+ depletion, increased activity of NCX produces an increased diastolic Ca2+ influx and SR Ca2+ loading21 or an increase in Ca2+ influx during EC coupling, which contributes to the Ca2+ transient and can produce a reduced dependence on L-type Ca2+ channel current during EC coupling.14 On the other hand, Satoh et al22 reported that 5 µmol/L KBR-7943, an inhibitor of reverse-mode NCX, had no effect on the magnitude of the Ca2+ transient or contraction in rat myocytes. Yang et al23 have reported that 5 µmol/L KBR-7943 decreases the [Ca2+]i transient in rabbit myocytes. Although KBR effects at concentrations of >1 µmol/L could be attributable to an effect of the drug on L-type Ca2+ channels, Yang et al23 also observed that submicromolar concentrations of KBR inhibited the increase in [Ca2+]i transient induced by endothelin-1 and have suggested that this effect is attributable to inhibition of an endothelin-1–induced increase in reverse-mode NCX. Unpublished work from our laboratory has indicated that 5-µmol/L KBR-7943 also produces a small but significant decrease in the magnitude of the Ca2+ transient in mouse ventricular myocytes. Some of these differences in experimental results may relate to species-dependent variations in expression of NCX,24 [Na+]i, and action potential duration, factors that influence reverse-mode NCX. Thus, NCX in cardiac myocytes can function in both forward and reverse modes, although the physiological importance of Ca2+ influx on NCX remains somewhat controversial.
A thorough understanding of the mechanisms and importance of NCX function is important, because the activity of this transporter is altered in heart hypertrophy and failure. Experiments in several laboratories have shown that hypertrophy in animals is associated with a switch to a fetal pattern of gene expression,25 including changes in actin and myosin isoforms, an increase in atrial natriuretic factor, a decrease in SR Ca2+-ATPase, and an increase in NCX expression. The possible functional importance of increased NCX expression and reduced SR Ca2+-ATPase activity has been studied in immature hearts and animal models of hypertrophy and failure. Haddock et al26 and Chin et al27 reported an apparent greater dependence on Ca2+ influx via NCX during an action potential and a reduced dependence on SR function for maintenance of the [Ca2+]i transient in newborn versus adult rabbit myocytes. Litwin and Bridge28 showed that in hypertrophied myocytes isolated from a peri-infarct area in a rabbit heart, NCX expression was increased and L-type Ca2+ current was decreased by 30% to 40%. In voltage-clamp studies, NCX seemed to provide Ca2+ influx to load the SR. The authors proposed that the increased activity of the NCX was maintaining SR Ca2+ loading in spite of some decrease in L-type Ca2+ current. O’Rourke et al29 found increased NCX and decreased SR Ca2+-ATPase expression in myocytes from a pacing-induced failure canine model and showed that forward function of NCX seemed to compensate partially for reduced SR Ca2+-ATPase function in reducing [Ca2+]i during a transient. Pogwizd et al30 found increased NCX expression in a rabbit model of left ventricular pressure and volume overload, with no change in SR Ca2+-ATPase or Ca2+ current density. Twitch amplitude was decreased by 21% and SR Ca2+ content was not altered, but the rate of decline of a caffeine-induced [Ca2+]i transient was accelerated. They proposed that increased NCX activity was reducing the amplitude of contraction and that increased NCX-dependent currents contributed to arrhythmias in this model.
In this issue of Circulation Research, Ito et al31 report studies of isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) and compensatory hypertrophy of 4 and 7 weeks’ duration. Although protein levels of NCX were increased at both 4 and 7 weeks, the SR Ca2+-ATPase to phospholamban protein ratio was depressed only in the 7-week AS myocytes. Under resting conditions, the amplitude of shortening and peak systolic [Ca2+]i were not different from controls in myocytes from animals at 7 weeks, although contraction, relaxation, and the decline of the Ca2+ transients were slower in the hypertrophied myocytes. In response to rapid pacing stimulation or exposure to high [Ca2+]o, cell shortening and peak systolic Ca2+ increased in controls, but the responses were depressed in 7-week AS myocytes, and SR Ca2+ content was reduced during rapid pacing in 7-week hypertrophied myocytes. These abnormalities cannot be ascribed to increased expression of NCX, because they were not present in 4-week AS myocytes. These results suggest that during hypertrophy in mice, reduced SR Ca2+-ATPase activity rather than increased NCX is the most important factor producing a functional abnormality during stress.
It is also known that the NCX protein may be increased and SR Ca2+-ATPase may be decreased in myocardium patients with heart failure,32 and this may have functional importance. Houser and colleagues33 34 35 have reported that in failing human ventricular myocytes isolated from explanted hearts, there is a late tonic component of contraction and [Ca2+]i transient. They suggest that this is attributable to influx of Ca2+ on NCX, possibly caused by increased expression of the exchanger and the prolonged action potential duration that is seen in human failing myocardium.36 This late tonic component could be inhibited by exposure to KBR-7943, providing some additional support for this hypothesis.33 This idea is also consistent with the early observations of Gwathmey et al,37 who noted a delayed secondary increase in the aequorin [Ca2+]i transient in failing myocardium. This was insensitive to ryanodine but was eliminated by verapamil, which could have shortened the prolonged action potential. The work of Flesch et al38 also suggests that enhanced expression of the exchanger could support contraction in failing myocytes by providing an additional source of Ca2+ influx to provide activation of the contractile elements and maintain SR Ca2+ loading.
On the other hand, studies by Schillinger et al39 and Hasenfuss et al40 have shown that failing human myocardium with an increased NCX exchanger but normal SR Ca2+-ATPase protein levels develop normal contractile force at rates of 40 to 60 min-1 but show a negative inotropic response to an increased pacing rate. To test the hypothesis that a reduced contractile force at high frequency of pacing is related to increased NCX activity, Schillinger et al41 report in this issue of Circulation Research important studies in which adenoviral transfection of the NCX gene in rabbit ventricular myocytes increased the level of expression of protein by 2- to 3-fold. This resulted in no significant change in fractional shortening during stimulation at 30 to 60 min-1 but caused a reduced positive inotropic response at faster rates of pacing. In support of the hypothesis that this effect was attributable to enhanced extrusion of Ca2+ from the myocyte by NCX, Schillinger et al show that SR Ca2+ content, as estimated from the contractile response to abrupt exposure to caffeine, was reduced in myocytes overexpressing the exchanger. These data support the hypothesis that increased expression of NCX in failing human myocardium promotes enhanced extrusion of Ca2+ from the myocyte, particularly at fast heart rates when action potential durations are relatively short, and suggest that this contributes, along with reduced expression of the SR Ca2+-ATPase, to the reduction in SR Ca2+ content that has been observed in failing myocardium.42 43
Do these findings, that a reduced Treppe response in rabbit myocardium is caused by an increased expression of NCX, mean that NCX activity, although helpful in maintaining diastolic function, is detrimental to systolic function in failing human myocardium? It is not certain that this is always the case. First, as mentioned previously, the [Na+]i and the action potential duration are of critical importance in determining the balance between Ca2+ influx and efflux on the exchanger. In failing human myocardium, the action potential is prolonged,35 especially at slow rates of stimulation,35 36 44 and the [Na+]i in failing human myocardium may be elevated. These factors could increase the importance of Ca2+ entry via reverse-mode NCX in failing human myocardium and produce a situation in which increased expression of NCX would, in fact, be beneficial rather than detrimental with respect to SR Ca2+ loading, especially at slow heart rates. This may explain why systolic function of failing myocardium is relatively normal at slow rates of stimulation39 and account for some of the benefits of ß-blocker therapy, which slows heart rate in patients with heart failure.
In summary, presently data are somewhat conflicting regarding the influence of increased expression of the NCX on myocyte function. The experiments of Schillinger et al41 are important in that they demonstrate for the first time that increased expression of NCX in rabbit myocytes with a relatively low [Na+]i and longer duration action potential can have a negative inotropic effect and produce depletion of SR Ca2+. This effect may be important in impairing contraction of failing human myocardium at rapid rates of contraction, but increased NCX expression may benefit systolic as well as diastolic function at slower rates of contraction, especially in myocardium with reduced activity of the SR Ca2+-ATPase.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Blaustein MP, Lederer WJ. Sodium/calcium exchange: its physiological implications. Physiol Rev. 1999;79:763–854.
2.
Barry WH, Rasmussen CAF Jr, Ishida H, Bridge
JHB. External Na-independent Ca extrusion in cultured
ventricular cells. J Gen Physiol. 1986;88:393–411.
3.
Bridge JHB, Smolley JR, Spitzer KW. The
relationship between charge movements associated with
ICa and INa-Ca
in cardiac myocytes. Science. 1990;248:376–378.
4.
Bers DM, Bassani JWM, Bassani RA. Competition
and redistribution among calcium transport systems in rabbit cardiac
myocytes. Cardiovasc Res. 1993;27:1772–1777.
5.
Bassani JWM, Bassani RA, Bers DM. Relaxation in
rabbit and rat cardiac cells: species-dependent differences in cellular
mechanisms. J Physiol (Lond). 1994;476:279–293.
6.
Yao A, Matsui H, Spitzer KW, Bridge JHB, Barry
WH. Sarcoplasmic reticulum and Na/Ca exchanger function during early
and late relaxation in ventricular myocytes. Am
J Physiol. 1997;273:H2765–H2773.
7.
Barry WH, Bridge JHB. Intracellular calcium
homeostasis in cardiac myocytes. Circulation. 1993;87:1806–1815.
8.
Su Z, Zou A, Nonaka A, Zubair I, Sanguinetti MC,
Barry WH. Influence of prior Na pump activity on pump and Na/Ca
exchange currents in mouse ventricular myocytes.
Am J Physiol. 1998;275:H1808–H1817.
9.
Barry WH, Hasin Y, Smith TW. Sodium pump
inhibition, enhanced calcium influx via sodium-calcium exchange, and
positive inotropic response in cultured heart cells. Circ
Res. 1985;56:231–241.
10.
Bers DM. Mechanisms contributing to the cardiac
inotropic effect of Na-pump inhibition and reduction of extracellular
Na. J Gen Physiol. 1987;90:479–504.
11.
Nuss HB, Houser SR. Sodium-calcium
exchange-mediated contractions in feline ventricular
myocytes. Am J Physiol. 1992;263:H1161–H1169.
12.
Goldhaber JI, Lamp ST, Walter DO, Garfinkel A,
Fukumoto GH, Weiss JN. Local regulation of the threshold for calcium
sparks in rat ventricular myocytes: role of sodium-calcium
exchange. J Physiol (Lond). 1999;520:431–438.
13. Litwin SE, Li J, Bridge JHB. Na-Ca exchange and the trigger for sarcoplasmic reticulum Ca release: studies in adult rabbit ventricular myocytes. Biophys J. 1998;75:359–371.[Medline] [Order article via Infotrieve]
14.
Yao A, Su Z, Nonaka A, Zubair I, Lu L, Philipson
KD, Bridge JHB, Barry WH. Effects of overexpression of the
Na+-Ca2+ exchanger on
[Ca2+]i transients in
murine ventricular myocytes. Circ Res. 1998;82:657–665.
15.
Levi AJ, Brooksby P, Hancox JC. A role for
depolarisation induced calcium entry on the Na-Ca exchange in
triggering intracellular calcium release and contraction in rat
ventricular myocytes. Cardiovasc Res. 1993;27:1677–1690.
16.
Lipp P, Niggli E. Sodium current-induced calcium
signals in isolated guinea-pig ventricular myocytes.
J Physiol (Lond). 1994;474:439–446.
17.
Kohomoto O, Levi AJ, Bridge JHB. Relation between
reverse sodium-calcium exchange and sarcoplasmic reticulum calcium
release in guinea pig ventricular cells. Circ
Res. 1994;74:550–554.
18.
Levesque PC, Leblanc N, Hume JR. Release of
calcium from guinea pig cardiac sarcoplasmic reticulum induced by
sodium-calcium exchange. Cardiovasc Res. 1994;28:370–378.
19. Sham JS, Cleemann L, Morad M. Gating of the cardiac Ca2+ release channel: the role of Na+ current and Na+-Ca2+ exchange. Science. 1992;25:850–853.
20.
Sipido KR, Maes M, Van de Werf F. Low efficiency
of Ca2+ entry through the
Na+-Ca2+ exchanger as
trigger for Ca2+ release from the sarcoplasmic
reticulum: a comparison between L-type Ca2+
current and reverse-mode
Na+-Ca2+ exchange.
Circ Res. 1997;81:1034–1044.
21.
Terracciano CM, Souza AI, Philipson KD, MacLeod
KT. Na+-Ca2+ exchange and
sarcoplasmic reticular Ca2+ regulation in
ventricular myocytes from transgenic mice overexpressing
the Na+-Ca2+ exchanger.
J Physiol (Lond). 1998;512:651–667.
22.
Satoh H, Ginsburg KS, Qing K, Terada H, Hayashi
H, Bers DM. KB-R7943 block of Ca2+ influx via
Na+/Ca2+ exchange does not
alter twitches or glycoside inotropy but prevents
Ca2+ overload in rat ventricular
myocytes. Circulation. 2000;101:1441–1446.
23. Yang H-T, Sakurai K, Sugawara H, Watanabe T, Norota I, Endoh M. Role of Na+/Ca2+ exchange in endothelin-1-induced increases in Ca2+ transient and contractility in rabbit ventricular myocytes: pharmacological analysis with KB-R7943. Br J Pharmacol. 1999;126:1785–1795.[Medline] [Order article via Infotrieve]
24. Su Z, Bridge JHB, Philipson KD, Spitzer KW, Barry WH. Quantitation of Na/Ca exchanger function in single ventricular myocytes. J Mol Cell Cardiol. 1999;31:1125–1135.[Medline] [Order article via Infotrieve]
25. Chien KR, Grace AA, Hunter JJ. Molecular basis of cardiac hypertrophy and heart failure. In: Chien KR, ed. Molecular Basis of Heart Disease. Philadelphia, Pa: WB Saunders; 1998:211–250.
26.
Haddock PS, Coetzee WA, Cho E, Porter L, Katoh H,
Bers DM, Jafri MS, Artman M. Subcellular
[Ca2+]i gradients during
excitation-contraction coupling in newborn rabbit
ventricular myocytes. Circ Res. 1999;85:415–427.
27. Chin TK, Christiansen GA, Caldwell JG, Thorburn J. Contribution of the sodium-calcium exchanger to contractions in immature rabbit ventricular myocytes. Pediatr Res. 1997;41:480–485.[Medline] [Order article via Infotrieve]
28.
Litwin SE, Bridge JH. Enhanced
Na+-Ca2+ exchange in the
infarcted heart: implications for excitation-contraction coupling.
Circ Res. 1997;81:1083–1093.
29.
O’Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin
R, Marbán E. Mechanisms of altered excitation-contraction
coupling in canine tachycardia-induced heart failure, I:
experimental studies. Circ Res. 1999;84:562–570.
30.
Pogwizd SM, Qi M, Yuan W, Samarel AM, Bers DM.
Upregulation of Na+/Ca2+
exchanger expression and function in an arrhythmogenic rabbit model of
heart failure. Circ Res. 1999;85:1009–1019.
31.
Ito K, Yan X, Tajima M, Su Z, Barry WH, Lorell
BH. Contractile reserve and intracellular calcium regulation in mouse
myocytes from normal and hypertrophied failing hearts. Circ
Res. 2000;87:588–595.
32.
Hasenfuss G. Alterations of calcium-regulatory
proteins in heart failure. Cardiovasc Res. 1998;37:279–289.
33.
Dipla K, Mattiello JA, Margulies KB, Jeevanandam
V, Houser SR. The sarcoplasmic reticulum and the
Na+/Ca2+ exchanger both
contribute to the Ca2+ transient of failing human
ventricular myocytes. Circ Res. 1999;84:435–444.
34.
Mattiello JA, Margulies KB, Jeevanandam V, Houser
SR. Contribution of reverse-mode sodium-calcium exchange to
contractions in failing human left ventricular myocytes.
Cardiovasc Res. 1998;37:424–431.
35.
Gaughan JP, Furukawa S, Jeevanandam V, Hefner CA,
Kubo H, Margulies KB, McGowan BS, Mattiello JA, Dipla K, Piacentino V
3rd, Li S, Houser SR. Sodium/calcium exchange contributes to
contraction and relaxation in failed human ventricular
myocytes. Am J Physiol. 1999;277:H714–H724.
36.
Beuckelmann DJ, Nabauer M, Erdmann E. Alterations
of K+ currents in isolated human
ventricular myocytes from patients with terminal heart
failure. Circ Res. 1993;73:379–385.
37.
Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ,
Feldman MD, Grossman W, Morgan JP. Abnormal intracellular calcium
handling in myocardium from patients with end-stage heart
failure. Circ Res. 1987;61:70–76.
38.
Flesch M, Schwinger RHG, Schiffer F, Frank K,
Sudkamp M, Kuhn-Regnier F, Arnold G, Bohm M. Evidence for functional
relevance of an enhanced expression of the
Na+-Ca2+ exchanger in
failing human myocardium. Circulation. 1996;94:992–1002.
39. Schillinger W, Lehnart SE, Prestle J, Preuss M, Pieske B, Maier LS, Meyer M, Just H, Hasenfuss G. Influence of SR Ca2+-ATPase and Na+-Ca2+-exchanger on the force-frequency relation. Basic Res Cardiol. 1998;93(suppl 1):38–45.
40.
Hasenfuss G, Schillinger W, Lehnart SE, Preuss M,
Pieske B, Maier LS, Prestle J, Minami K, Just H. Relationship between
Na+-Ca2+–exchanger protein
levels and diastolic function of failing human
myocardium. Circulation. 1999;99:641–648.
41. Schillinger W, Janssen PML, Emami S, Henderson SA, Ross RS, Teucher N, Zeitz O, Philipson KD, Prestle J, Hasenfuss G. Impaired contractile performance of cultured rabbit ventricular myocytes after adenoviral gene transfer of Na+-Ca2+ exchanger. Circ Res. 2000;87:000–000.
42.
Pieske B, Maier LS, Bers DM, Hasenfuss G.
Ca2+ handling and sarcoplasmic reticulum
Ca2+ content in isolated failing and nonfailing
human myocardium. Circ Res. 1999;85:38–46.
43. Lindner M, Erdmann E, Beuckelmann DJ. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol. 1998;30:743–749.[Medline] [Order article via Infotrieve]
44.
Sipido KR, Stankovicova T, Flameng W, Vanhaecke
J, Verdonck F. Frequency dependence of Ca2+
release from the sarcoplasmic reticulum in human
ventricular myocytes from end-stage heart failure.
Cardiovasc Res. 1998;37:478–488.
This article has been cited by other articles:
 |
|
 |
|
  B. N. Eigel, H. Gursahani, and R. W. Hadley Na+/Ca2+ exchanger plays a key role in inducing apoptosis after hypoxia in cultured guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1466 - H1475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Brette and C. Orchard T-Tubule Function in Mammalian Cardiac Myocytes Circ. Res., June 13, 2003; 92(11): 1182 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H. Barry and E. M. Gilbert How Do {beta}-Blockers Improve Ventricular Function in Patients With Congestive Heart Failure? Circulation, May 20, 2003; 107(19): 2395 - 2397. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pieske and S. R Houser [Na+]i handling in the failing human heart Cardiovasc Res, March 15, 2003; 57(4): 874 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sjaastad, J A. Wasserstrom, and O. M Sejersted Heart failure - a challenge to our current concepts of excitation-contraction coupling J. Physiol., January 1, 2003; 546(1): 33 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pieske, L. S. Maier, V. Piacentino III, J. Weisser, G. Hasenfuss, and S. Houser Rate Dependence of [Na+]i and Contractility in Nonfailing and Failing Human Myocardium Circulation, July 23, 2002; 106(4): 447 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Philipson Na+-Ca2+ Exchange: Three New Tools Circ. Res., February 8, 2002; 90(2): 118 - 119. [Full Text] [PDF]
|
|
|
|
|
|
M. Shigekawa and T. Iwamoto Cardiac Na+-Ca2+ Exchange : Molecular and Pharmacological Aspects Circ. Res., May 11, 2001; 88(9): 864 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Wang, B. Nolan, W. Kutschke, and J. A. Hill Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy J. Biol. Chem., May 18, 2001; 276(21): 17706 - 17711. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||