FASEB J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by TAKIMOTO, E.
Right arrow Articles by KOMURO, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by TAKIMOTO, E.
Right arrow Articles by KOMURO, I.
(The FASEB Journal. 2002;16:373-378.)
© 2002 FASEB

Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload

EIKI TAKIMOTO, ATSUSHI YAO, HARUHIRO TOKO*, HIROYUKI TAKANO*, MASAKI SHIMOYAMA, MAKOTO SONODA, KOJI WAKIMOTO{dagger}, TOSHIYUKI TAKAHASHI, HIROSHI AKAZAWA*, MIHO MIZUKAMI*, TOSHIO NAGAI*, RYOZO NAGAI and ISSEI KOMURO*1

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan;
* Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan; and
{dagger} Discovery Laboratory, Tanabe Seiyaku Co., Ltd., Yodokawa-ku, Osaka 532-8505, Japan

1Correspondence: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1–8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: komuro-tky{at}umin.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Na+-Ca2+ exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells, including cardiac myocytes. However, the pathophysiological role of NCX in the heart is still unclear because of the lack of known specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta, and examined cardiac function and morphology 3 wk after operation. Although there was no difference in cardiac function between sham-operated KO mice and sham-operated wild-type (WT) mice, KO mice showed higher left ventricular pressure and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca2+-ATPase were reduced by pressure overload in left ventricles of WT but not of KO mice. However, hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.—Takimoto, E., Yao, A., Toko, H., Takano, H., Shimoyama, M., Sonoda, M., Wakimoto, K., Takahashi, T., Akazawa, H., Mizukami, M., Nagai, T., Nagai, R., Komuro, I. Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload.


Key Words: Na+-Ca2+ exchanger • sarcoplasmic reticulum • knockout mice • NCX


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ACCUMULATING EVIDENCE SUGGESTS that alterations of excitation contraction (EC) coupling cause heart failure (1) . Since cytosolic free calcium ([Ca2+]i) plays a critical role in EC coupling, [Ca2+]i levels are tightly regulated by multiple organs in cardiac myocytes. In EC coupling, calcium entering from extracellular space via L-type Ca2+ channels triggers release of calcium from the sarcoplasmic reticulum (SR), which causes a large increase in [Ca2+]i and muscle contraction. The increase in [Ca2+]i is immediately followed by calcium removal, resulting in muscle relaxation. Calcium removal is accomplished by extrusion to extracellular space by sarcolemmal sodium calcium exchanger (NCX) and by reuptake into SR by the SR calcium pump (SERCA2). Systolic and diastolic dysfunction of the heart may result from disturbed calcium homeostasis with altered content or function of these calcium-regulating proteins (2) .

NCX of the plasma membrane is an electrogenic transporter. Three mammalian isoforms of NCX (NCX1, NCX2, and NCX3) have been isolated, and NCX1 is expressed at high levels in the heart (3 4 5 6 7 8) . Extrusion of calcium depends on the concentration of extracellular sodium; the exchange is accomplished in a ratio of three sodium to one calcium, thereby generating an inward current (forward mode). In the initial phase of EC coupling, however, Na+-Ca2+ exchange may occur in the opposite direction (reverse mode) (1 , 9) . NCX is thought to contribute ~20% of [Ca2+]i decrease during relaxation and 80% of calcium movement can be attributed to SERCA2 in cardiac myocytes (9 10 11) , although this ratio may vary among species during developmental stages and in pathological situations (12 13 14 15 16 17 18) . Alterations in expression and function of NCX have been reported in pathological hearts of human and animal models (19 20 21 22 23 24 25 26 27) . In failing human hearts, expression of NCX has been reported to be increased whereas that of SERCA2 is reduced (22 , 23) . In contrast, expression of NCX is down-regulated in the heart with hyperthyroidism and that of SERCA2 is increased (26 , 27) . Although the significance of Na+-Ca2+ exchange in EC coupling is thought to be important, it is unclear whether the change of expression levels of NCX causes these pathological status because there are no known highly specific inhibitors or stimulators of NCX.

We previously reported that homozygous NCX1-deficient mice die in utero between embryonic day 9 and 10 (28) . In null mutant hearts, there exists no forward or reverse mode of the Na+-Ca2+ exchanger activity: the heart does not beat and cardiac myocytes show apoptosis. These findings suggest that NCX1 is required for heartbeat and survival of cardiac myocytes in embryos. To clarify the role of NCX1 in cardiac function and the development of cardiac hypertrophy in response to pressure overload, we analyzed heterozygous mutant of NCX1 knockout (KO) mice. Heterozygous mutant mice were apparently healthy but showed a marked difference in cardiac performance and cardiac hypertrophy vs. wild-type (WT) mice (28) .


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal models
All protocols were approved by local institutional guidelines. NCX knockout mice were generated as described previously (28) . Male heterozygous mutants (KO) and WT littermates of 9-wk-old (21–24 g) were used in the present study. Pressure overload was produced by constricting transverse aorta (29) . Mice were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) and xylazine (5 mg/kg), and respiration was artificially controlled with a tidal volume of 0.2 ml and a respiratory rate of 110 breaths/min. The transverse aorta was constricted with 7–0 nylon strings by ligating the aorta with a blunted 27 gauge needle, which was removed later. After aortic constriction, the chest was closed and mice were allowed to recover from anesthesia. We confirmed that the magnitude of initial pressure elevation after aortic banding was identical in NCX KO mice and WT mice. The surgeon had no information about the mice used in this study.

Physiological analysis
For catheterization analysis, the right carotid artery was cannulated under anesthesia by a Millar Mikro-Tip transducer with an outer diameter of 0.47 mm (model SPR-612, Millar Instruments, Houston, TX), which was then advanced into the left ventricle. Pressure signals were recorded using a MacLab 3.6/s data acquisition system (AD Instruments, Milford, MA) with a sampling rate of 2000 Hz. Transthoracic echocardiography was performed with HP Image Point (Hewlett Packard, Palo Alto, CA) with a 10 MHz transducer (30) . The quantitative measurements represent consensus estimates of two investigators (E.T. and H.T.), and interobserver variability was <10%. To compare cardiac function among the groups, recordings were made under identical conditions with heart rates at 200–250 bpm (catheterization and Doppler echo analysis) and at 250–300 bpm (M mode echo analysis).

Histological analysis
For histological analysis, hearts were fixed with 10% formalin overnight, then embedded in paraffin, sectioned at 4 µm thickness, and stained by the Azan method for collagen.

RNA analysis
Total RNA was extracted from left ventricles of mice with RNA ZolB (Teltest Ltd., Porirua, N. Zealand). For Northern blot analysis, 10 µg of total RNA was separated on a 1.2% agarose-formaldehyde gel and blotted onto a Hybond-N membrane (Amersham, Little Chalfont, UK). Probes for SERCA2 and the {alpha}1 subunit of dihydropyridine sensitive Ca2+ channel receptor (DHPR) were as described (32 , 33) . cDNA of RyR2 was a gift from Takeshima (Kurume Medical College) (34) . The cDNAs were labeled by random priming with [{alpha}-32P] dCTP. Quantification of hybridized bands was carried out using Fuji image analyzer (Fujix bas 2000; Fujifilm).

Statistical analysis
Results are expressed as the mean value ± SE. Multiple comparisons among three or more groups were carried out by one-way ANOVA and Fisher’s exact test for post hoc analysis. A value of P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Physiological analysis
Pressure study revealed no difference in systolic left ventricular pressure (LVP), end-diastolic pressure (EDP), and positive and negative first derivatives of left ventricular pressure (dP/dt, -dP/dt) between sham-operated KO mice and sham-operated WT mice (sham in Table 1 ). Echocardiography also indicated there was no significant difference in cardiac morphology such as interventricular septal wall thickness (IVST), LV posterior wall thickness, LV end-diastolic dimension (LVDd), or LV end-systolic dimension (LVDs) between the two animal groups. Cardiac functions exemplified by ejection fraction (EF), peak early diastolic transmitral velocity (E), E to peak late diastolic transmitral velocity (E/A), and deceleration time of early diastolic transmitral velocity (DCT) of KO mice were not different from those of WT mice. These results suggest that there is no difference in baseline cardiac functions between the two groups.


View this table:
[in this window]
[in a new window]
  		Table 1. Physiological analysisa

To elucidate the role of NCX under pathological conditions, we imposed pressure overload on the heart by constricting transverse aorta (TAC) and performed analysis 3 wk after operation. Both mice showed an increase in peak LVP and EDP (Table 1 , Fig. 1 A). The increase in both pressure parameters was more prominent in KO mice than in WT mice. Moreover, dP/dt was significantly increased only in KO and not in WT mice (Table 1 , Fig. 1B ). These data suggest that the heart of KO mice responds more strongly to pressure overload and that cardiac systolic function is enhanced in KO mice in response to pressure overload. Minimal dP/dt, which reflects cardiac relaxant function, was also increased more markedly in KO mice than WT mice (Table 1 , Fig. 1B ). However, KO mice showed a diastolic dip and plateau pattern of LVP, which suggests the existence of ‘restrictive’ diastolic dysfunction (Fig. 1A ) (35) . Echocardiography revealed that EF was reduced by TAC in WT but not in KO mice (Table 1) . Although LVDd was enlarged by TAC to the same extent in both WT and KO mice, LVDs was larger in WT than KO mice (Table 1) . LV wall thickness was more increased by TAC in KO mice than in WT mice (Table 1) . LV inflow pattern by Doppler was not changed by TAC in WT mice whereas KO mice showed pseudonormalization of LV inflow pattern characterized by increased E wave and short DCT (Table 1 , Fig. 1C ). These results also suggest the existence of restrictive diastolic dysfunction in KO mice (36) .



View larger version (80K):
[in this window]
[in a new window]
  		Figure 1. Representative recordings of left ventricular pressure (LVP) (A) and first derivatives of LVP (dP/dt) (B) by catheterization analysis and LV inflow pattern (transmitral velocity) (C) by Doppler echocardiographic analysis. WT TAC, wild-type TAC-operated mouse (upper panels); NCX KO TAC, NCX knockout TAC-operated mouse (lower panels). A, B) Systolic LVP, maximal dP/dt, and minimal dP/dt were increased in KO mouse. Diastolic LVP in KO mouse revealed a dip and plateau pattern (arrow). C) Increased peak of E wave with short deceleration time was observed in KO mice. E, Early transmitral velocity; A, late diastolic transmitral velocity due to atrial contraction.

Histological analysis
There was no significant difference in body weight (BW) among WT and KO mice before or after pressure overload (Fig. 2 ). At 3 wk after TAC, left ventricular weight to BW ratio was increased in both KO and WT mice, but the increase was more prominent in KO vs. WT mice (Fig. 2A ). Light microscopic analysis revealed there was no fibrosis in the hearts of sham-operated mice of either group; 3 wk after the TAC operation, fibrosis was recognized in the heart of KO mice (Fig. 2B ).



View larger version (70K):
[in this window]
[in a new window]
  		Figure 2. Cardiac hypertrophy and fibrosis. A) There was no significant difference in body weight (BW). LV weight normalized to body weight (LVW/BW) was increased more by TAC in KO than in WT mice. Data are expressed as mean ± SE. S indicates sham-operated mice and T indicates TAC-operated mice. n = 6 for WT sham and WT TAC; n = 4 for KO sham and KO TAC. B) Azan staining revealed that interstitial collagen accumulation by TAC was much greater in KO than WT mice. There were no differences between sham-operated WT mice and sham-operated KO mice. Bar = 200 µm.

RNA analysis
To determine genetic alterations that underlie these cardiac functional changes by pressure overload, mRNA levels of calcium-regulating proteins were examined by Northern blot analysis. There were no significant differences in ventricular mRNA levels of SERCA2, DHPR, and RyR2 between sham-operated KO and sham-operated WT mice (Fig. 3 ). At 3 wk after TAC, however, expression levels of SERCA2 were significantly reduced in the left ventricle of WT mice but remained unchanged in KO mice (Fig. 3A ). Expression levels of DHPR were decreased by TAC in ventricles of both KO and WT mice to the same extent (Fig. 3B ). Expression levels of RyR2 were not changed by TAC in either KO or WT mice (Fig. 3C ).



View larger version (24K):
[in this window]
[in a new window]
  		Figure 3. Alterations in mRNA levels of calcium regulatory proteins. SERCA2 mRNA levels were significantly reduced by pressure overload in WT mice but unchanged in KO mice (A). DHPR mRNA levels were decreased by pressure overload in both WT and KO mice (B). RyR2 mRNA levels were not significantly changed by TAC in either WT or KO mice (C). There were no differences in expression levels of SERCA2, DHPR, or RyR2 between sham-operated WT mice and sham-operated KO mice. mRNA levels were normalized with the intensity of GAPDH. Data are expressed as mean ± SE. S indicates sham-operated mice and T indicates TAC-operated mice. n = 6 for WT sham and WT TAC; n = 4 for KO sham and KO TAC.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, although there was no significant difference in baseline cardiac function between KO and WT mice, KO mice showed more markedly elevated peak LVP than WT mice in response to pressure overload. In WT mice, cardiac functions exemplified by peak dP/dt and EF were deteriorated in response to pressure load. In KO mice, by contrast, these parameters representative of cardiac function were increased. Therefore, the more increased peak LVP in KO mice is not due to procedural bias but to enhanced contractility. In response to pressure overload, the heart develops hypertrophy as an adaptation to reduce wall stress and maintain cardiac function. Both NCX and SERCA2 work in concert to reduce cytosolic Ca2+ levels during diastolic phase, and therefore alterations in expression levels of these proteins may cause cardiac dysfunction (4 , 9 , 19 20 21 22 23 24 25) . Decreased expression of SERCA2 was observed in many models of cardiac hypertrophy and failure (37 , 38) . Recent studies demonstrate that NCX is up-regulated in hearts of pressure overload-induced hypertrophy and cardiomyopathy (19 20 21 22 23 24 25) . An increase in NCX without a decrease in SERCA2 was reported in human (24) and rabbit (25) hearts with systolic dysfunction. Recently many reports have demonstrated genetically engineered mouse models in which expressions of SR calcium regulatory proteins are modified (39 40 41 42) . Heterozygous mutants of SERCA2 null mice revealed impaired systolic function (39) whereas transgenic mice overexpressing SERCA2 revealed enhanced systolic function (40) . Null mutants of phospholamban, which negatively regulates SERCA2 activity, revealed better cardiac performance (41) but phospholamban-overexpressed mice revealed impaired cardiac function (42) . In this study, NCX mutant mice showed enhanced cardiac function in response to pressure overload. These observations and results suggest that not only a decrease in SERCA2, but also an increase in NCX, may be a cause of depressed systolic performance in the pathological conditions such as pressure overload-induced cardiac hypertrophy or ischemia/perfusion injury.

The systolic [Ca2+]i rise is initiated by the Ca2+ influx through L-type Ca2+ channels and enhanced by subsequent release from SR, called Ca2+-induced Ca2+ release. Northern blot analysis showed that expression levels of DHPR, SERCA2, and RyR2 in the heart of sham-operated KO mice were identical to those of sham-operated WT mice. Northern blot analysis and Western blot analysis revealed that NCX in the heart of heterozygous KO mice was ~half of that of WT mice at mRNA and protein levels (28) . The mRNA level of SERCA2 in the left ventricle was reduced in WT hearts but preserved in KO hearts after pressure overload. On the other hand, expression levels of DHPR and RYR2 were similar between WT and KO mice after pressure overload. Earlier studies have shown that expression of NCX is increased and that of SERCA2 is decreased in failing hearts and hypothyroid hearts and that an opposite response is observed in hyperthyroid hearts. Because both proteins are involved in Ca2+ removal from cytoplasm, it seems that an increase in NCX may compensate for less effective SR Ca2+ uptake by a decrease in SERCA2. As pressure overload-induced increase in cytosolic Ca2+ may be enhanced by reduced expression of NCX, there is the possibility these changes may be compensated by up-regulation of SERCA2. Regulatory mechanisms of Ca2+-handling protein contents (including RyR and DHPR as well as NCX and SERCA2) remain to be determined.

In this study, NCX KO mice showed enhanced cardiac function such as higher LVP, dP/dt, and -dP/dt compared with WT mice. These results suggest that a decrease in NCX-driven calcium efflux may cause increases in calcium content in SR and systolic [Ca2+]i. An earlier study reported that the SR Ca2+ content of transgenic mice overexpressing NCX was larger than that of wild-type mice (43) . In contrast, in rabbit ventricular myocytes overexpressing NCX, SR Ca2+ content was reduced and fractional shortening of the myocytes by edge detection was impaired (44) . Even though the reason for this discrepancy is not known, since the high [Na+]i in myocytes of small mammals (i.e., mice and rats) has been reported to favor Ca2+ entry via the reverse mode mechanism of NCX during the action potential (9) , the NCX-mediated Ca2+ influx may become pronounced in transgenic animals overexpressing NCX. Therefore, reuptake of Ca2+ into SR during the action potential may be increased despite an enhanced forward mode function of NCX in transgenic mice. Decreased activity of NCX with increased activity of SERCA2 was reported in the rat heart showing hyperthyroidism (27) . The results of this study suggest that the decrease in NCX and increase in SERCA2 may underlie the cardiac hyperperformance observed in hyperthyroidism.

Hypertrophied and failing hearts show diastolic dysfunction, which usually results from impairment of both LV relaxation and LV compliance. The process of calcium removal from cytosol determines LV relaxation while structural changes such as interstitial fibrosis and LV wall thickness reduce LV compliance (45) . Since SERCA2 expression levels were reduced in WT mice but not in KO mice, the SR Ca2+ pump activity may be higher in KO than WT mice. Therefore, both a decrease in NCX and an increase in SERCA2 may contribute to the better diastolic relaxation in NCX KO mice. However, catheterization and Doppler echocardiographic analysis revealed that LV compliance was impaired in NCX KO mice in response to pressure overload. Blood pressure was more markedly elevated in KO mice than WT mice, resulting in more marked LV hypertrophy with severe interstitial fibrosis in KO mice. These anatomical changes may cause this type of diastolic dysfunction. In summary, reduced levels of NCX may lead to an increase in cytosolic and SR Ca2+ content, which results in supernormalized systolic and diastolic relaxation function in response to pressure overload. These results suggest that NCX as well as SERCA2 plays a key role in cardiac function in pathological situations. Therefore, reducing NCX function may provide a novel therapeutic approach for heart failure under certain pathological conditions.


   ACKNOWLEDGMENTS
 
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan, and by the Program for promotion of Fundamental Studies in Health Science of the Organization for Drug ADR Relief, R&D Promotion, and Product Review of Japan.

Received for publication September 7, 2001. Revision received November 27, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Barry, W. H., Bridge, J. H. (1993) Intracellular calcium homeostasis in cardiac myocytes. Circulation 87,1806-1815[Abstract/Free Full Text]
  2. Hasenfuss, G. (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc. Res. 37,279-289[Free Full Text]
  3. Nicoll, D. A., Longoni, S., Philipson, K. D. (1990) Molecular cloning and functional expression of the cardiac sarcolemmal Na+-Ca2+ exchanger. Science 250,562-565[Abstract/Free Full Text]
  4. Komuro, I., Wenninger, K. E., Philipson, K. D., Izumo, S. (1992) Molecular cloning and characterization of the human cardiac Na+-Ca2+ exchanger cDNA. Proc. Natl. Acad. Sci. USA 89,4769-4773[Abstract/Free Full Text]
  5. Li, Z., Matsuoka, S., Hryshko, L. V., Nicoll, D. A., Bersohn, M. M., Burke, E. P., Lifton, R. P., Philipson, K. D. (1994) Cloning of the NCX2 isoform of the plasma membrane Na+-Ca2+ exchanger. J. Biol. Chem. 269,17434-17439[Abstract/Free Full Text]
  6. Nicoll, D. A., Quednau, B. D., Qui, Z., Xia, Y. R., Lusis, A. J., Philipson, K. D. (1996) Cloning of a third mammalian Na+-Ca2+ exchanger, NCX3. J. Biol. Chem. 271,24914-24921[Abstract/Free Full Text]
  7. Kofuji, P., Hadley, R. W., Kieval, R. S., Lederer, W. J., Schulze, D. H. (1992) Expression of the Na+-Ca2+ exchanger in diverse tissues: a study using the cloned human cardiac Na+-Ca2+ exchanger. Am. J. Physiol. 263,C1241-C1249[Abstract/Free Full Text]
  8. Quednau, B. D., Nicoll, D. A., Philipson, K. D. (1997) Tissue specificity and alternative splicing of the Na+-Ca2+ exchanger isoforms NCX1, NCX2 and NCX3 in rat. Am. J. Physiol. 272,C1250-C1261[Abstract/Free Full Text]
  9. Bers, D. M. (2000) Calcium fluxes involved in control of cardiac myocyte contraction. Circ. Res. 87,275-281[Free Full Text]
  10. Bers, D. M., Bridge, J. H. (1989) Relaxation of rabbit ventricular muscle by Na+-Ca2+ exchange and sarcoplasmic reticulum calcium pump. Circ. Res. 65,334-342[Abstract/Free Full Text]
  11. Bers, D. M., Lederer, W. J., Berlin, J. R. (1990) Intracellular Ca transients in rat cardiac myocytes: role of Na+-Ca2+ exchange in excitation-contraction coupling. Am. J. Physiol. 258,C944-C954[Abstract/Free Full Text]
  12. Bers, D. M., Bassani, J. W., Bassani, R. A. (1993) Competition and redistribution among calcium transport systems in rabbit cardiac myocytes. Cardiovasc. Res. 27,1772-1777[Free Full Text]
  13. Negretti, N., O’Neill, S. C., Eisner, D. A. (1993) The relative contributions of different intracellular and sarcolemmal systems to relaxation in rat ventricular myocytes. Cardiovasc. Res. 27,1826-1830[Abstract/Free Full Text]
  14. Klitzner, T. S. (1991) Maturational changes in excitation-contraction coupling in mammalian myocardium. J. Am. Coll. Cardiol. 17,218-225[Abstract]
  15. Seguchi, M., Harding, J. A., Jarmakani, J. M. (1986) Developmental change in the function of sarcoplasmic reticulum. J. Mol. Cell. Cardiol. 18,189-195[CrossRef][Medline]
  16. Morgan, J. P. (1991) Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N. Engl. J. Med. 325,625-632[Medline]
  17. Vetter, R., Studer, R., Reinecke, H., Kolar, F., Ostadalova, I., Drexler, H. (1995) Reciprocal changes in the postnatal expression of the sarcolemmal Na+-Ca2+ exchanger and SERCA2 in rat heart. J. Mol. Coll. Cardiol. 27,1689-1701
  18. Koban, M. U., Moorman, A. F., Holtz, J., Yacoub, M. H., Boheler, K. R. (1998) Expressional analysis of the cardiac Na+-Ca2+ exchanger in rat development and senescence. Cardiovasc. Res. 37,405-423[Abstract/Free Full Text]
  19. Hatem, S. N., Sham, J. S., Morad, M. (1994) Enhanced Na+-Ca2+ exchange activity in cardiomyopathic Syrian hamster. Circ. Res. 74,253-261[Abstract/Free Full Text]
  20. Kent, R. L., Rozich, J. D., McCollam, P. L., McDermott, D. E., Thacker, U. F., Menick, D. R., McDermott, P. J., Cooper, V. I. G. (1993) Rapid expression of the Na+-Ca2+ exchanger in response to cardiac pressure overload. Am. J. Physol. 265,H1024-H1029[Abstract/Free Full Text]
  21. Studer, R., Reinecke, H., Bilger, J., Eschenhagen, T., Bohm, M., Hasenfuss, G., Just, H., Holtz, J., Drexler, H. (1994) Gene expression of the cardiac Na+-Ca2+ exchanger in end-stage human heart failure. Circ. Res. 75,443-453[Abstract/Free Full Text]
  22. Reinecke, H., Studer, R., Vetter, R., Holtz, J., Drexler, H. (1996) Na+/Ca2+ exchange activity in patients with end-stage heart failure. Cardiovasc. Res. 31,48-54[CrossRef][Medline]
  23. O’Rourke, B., Kass, D. A., Tomaselli, G. F., Kaab, S., Tunin, R., Marban, E. (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure. I: Experimental studies. Circ. Res. 84,562-570[Abstract/Free Full Text]
  24. Hasenfuss, G., Schillinger, W., Lehnart, S. E., Preuss, M., Pieske, B., Maier, L. S., Prestle, J., Minami, K., Just, H. (1999) Relationship between Na+-Ca2+ exchanger protein levels and diastolic function of failing human myocardium. Circulation 99,641-648[Abstract/Free Full Text]
  25. Pogwizd, S. M., Qi, M., Yuan, W., Samarel, A. M., Bers, D. M. (1999) Upregulation of Na+/Ca2+ exchanger expression and function in an arrhythmogenic rabbit model of heart failure. Circ. Res. 85,1009-1019[Abstract/Free Full Text]
  26. Reed, T. D., Babu, G. J., Ji, Y., Zilberman, A., Ver Heyen, M., Wuytack, F., Periasamy, M. (2000) The expression of SR calcium transport ATPase and the Na+-Ca2+ exchanger are antithetically regulated during mouse cardiac development and in hypo/hyperthyroidism. J. Mol. Cell. Cardiol. 32,453-464[CrossRef][Medline]
  27. Cernohorsky, J., Kolar, F., Pelouch, V., Korecky, B., Vetter, R. (1998) Thyroid control of sarcolemmal Na+/Ca2+ exchanger and SR Ca2+ ATPase in developing rat heart. Am. J. Physiol. 275,H264-H273[Abstract/Free Full Text]
  28. Wakimoto, K., Kobayashi, K., Kuro-o, M., Yao, A., Iwamoto, T., Yanaka, N., Kita, S., Nishida, A., Azuma, S., Toyoda, Y., Omori, K., Imahie, H., Oka, T., Kudoh, S., Kohmoto, O., Yazaki, Y., Shigekawa, M., Imai, Y., Nabeshima, Y., Komuro, I. (2000) Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heart beat. J. Biol. Chem. 275,36991-36998[Abstract/Free Full Text]
  29. Harada, K., Komuro, I., Zou, Y., Kudoh, S., Kijima, K., Matsubara, H., Sugaya, T., Murakami, K., Yazaki, Y. (1998) Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type 1a knockout mice. Circ. Res. 82,779-785[Abstract/Free Full Text]
  30. Taffet, G. E., Hartley, C. J., Wen, X., Pham, T., Michael, L. H., Entman, M. L. (1996) Noninvasive indexes of cardiac systolic and diastolic function in hyperthyroid and senescent mouse. Am. J. Physol. 270,H2204-H2209[Abstract/Free Full Text]
  31. Yao, A., Su, Z., Nonaka, A., Zubair, I., Lu, L., Philipson, K. D., Bridge, J. H., Barry, W. H. (1998) Effects of overexpression of the Na+-Ca2+ exchanger on [Ca2+]i transients in murine ventricular myocytes. Circ. Res. 82,657-665[Abstract/Free Full Text]
  32. Shimoyama, M., Hayashi, D., Takimoto, E., Zou, Y., Oka, T., Uozumi, H., Kudoh, S., Shibasaki, F., Yazaki, Y., Nagai, R., Komuro, I. (1999) Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. Circulation 100,2449-2454[Abstract/Free Full Text]
  33. Takahashi, T., Allen, P. D., Lacro, R. V., Marks, A. R., Dennis, A. R., Schoen, F. J., Grossman, W., Marsh, J. D., Izumo, S. (1992) Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure. J. Clin. Invest. 90,927-935
  34. Takeshima, H., Komazaki, S., Hirose, K., Nishi, M., Noda, T., Iino, M. (1998) Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2. EMBO J 17,3309-3316[CrossRef][Medline]
  35. Benotti, J. R., Grossman, W., Cohn, P. F. (1980) Clinical profile of restrictive cardiomyopathy. Circulation 61,1206-1212[Abstract/Free Full Text]
  36. DeMaria, A. N., Wisenbaugh, T. W., Smith, M. D., Harrison, M. R., Berk, M. R. (1991) Doppler echocardiographic evaluation of diastolic dysfunction. Circulation 84,1288-1295
  37. Komuro, I., Kurabayashi, M., Shibazaki, Y., Takaku, F., Yazaki, Y. (1989) Molecular cloning and characterization of a Ca2+ + Mg2+-dependent adenosine triphosphatase from rat cardiac sarcoplasmic reticulum. Regulation of its expression by pressure overload and developmental stage. J. Clin. Invest. 83,1102-1108
  38. Lompre, A. M., Anger, M., Levitsky, D. (1994) Sarco(endo) plasmic reticulum calcium pumps in the cardiovascular system: function and gene expression. J. Mol. Cell. Cardiol. 26,1109-1121[CrossRef][Medline]
  39. Periasamy, M., Reed, T. D., Liu, L. H., Ji, Y., Loukianov, E., Paul, R. J., Nieman, M. L., Riddle, T., Duffy, J. J., Doetschman, T., Lorenz, J. N., Shull, G. E. (1999) Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+ ATPase isoform 2 (SERCA2) gene. J. Biol. Chem. 274,2556-2562[Abstract/Free Full Text]
  40. Baker, D. L., Hashimoto, K., Grupp, I. L., Ji, Y., Reed, T., Loukianov, E., Grupp, G., Bhagwhat, A., Hoit, B., Walsh, R., Marban, E., Periasamy, M. (1998) Targeted overexpression of the sarcoplasmic reticulum Ca2+ ATPase increases cardiac contractility in transgenic mouse hearts. Circ. Res. 83,1205-1214[Abstract/Free Full Text]
  41. Lorenz, J. N., Kranias, E. G. (1997) Regulatory effects of phospholamban on cardiac function in intact mice. Am. J. Physiol. 273,H2826-H2831
  42. Kadambi, V. J., Ponniah, S., Harrer, J. M., Hoit, B. D., Dorn, G. W., II, Walsh, R. A., Kranias, E. G. (1996) Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J. Clin. Invest. 97,533-539[Medline]
  43. Terraciano, C. M., Souza, A. I., Philipson, K. D., MacLeod, K. T. (1998) Na+-Ca2+ exchanger and sarcoplasmic reticular Ca2+ regulation in ventricular myocytes from transgenic mice overexpressing the Na+-Ca2+ exchanger. J. Physiol. (London) 512,651-667[Abstract/Free Full Text]
  44. Schillinger, W., Janssen, P. M., Emami, S., Henderson, S. A., Ross, R. S., Teucher, N., Zeitz, O., Philipson, K. D., Prestle, J., Hasenfuss, G. (2000) Impaired contractile performance of cultured rabbit ventricular myocytes after adenoviral gene transfer of Na+-Ca2+ exchanger. Circ. Res. 87,581-587[Abstract/Free Full Text]
  45. Gaasch, W. H., Levine, H. J., Quinones, M. A., Alexander, J. K. (1976) Left ventricular compliance: mechanisms and clinical implications. Am. J. Cardiol. 38,645-653[CrossRef][Medline]



This article has been cited by other articles:


Home page
 CirculationHome page
H. E. Cingolani and I. L. Ennis
Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy
Circulation, March 6, 2007; 115(9): 1090 - 1100.
[Full Text] [PDF]

Home page
 FASEB J.Home page
J. BORLAK and T. THUM
Hallmarks of ion channel gene expression in end-stage heart failure
FASEB J, September 1, 2003; 17(12): 1592 - 1608.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by TAKIMOTO, E.
Right arrow Articles by KOMURO, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by TAKIMOTO, E.
Right arrow Articles by KOMURO, I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS