Skip Navigation

European Journal of Heart Failure 2005 7(5):739-747; doi:10.1016/j.ejheart.2004.10.007
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Prunier, F.
Right arrow Articles by Mercadier, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Prunier, F.
Right arrow Articles by Mercadier, J.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2004 European Society of Cardiology

Left ventricular SERCA2a gene down-regulation does not parallel ANP gene up-regulation during post-MI remodelling in rats

Fabrice Pruniera,1, Ying Chena, Barnabas Gellena, Michéle Heimburgera, Christine Choqueuxa, Brigitte Escoubetb, Jean-Baptiste Michela and Jean-Jacques Mercadiera,*

a INSERM U 460, Groupe Hospitalier Bichat-Claude Bernard, Paris, France
b INSERM U 426, Faculté de Médecine Xavier Bichat, CEFI, IFR 02, Faculté de Médecine Xavier Bichat, Paris, France, Service de Physiologie—Explorations Fonctionnelles, Groupe Hospitalier Bichat-Claude Bernard, A.P.-H.P., Paris, France

* Corresponding author. Tel.: +33 1 40 25 86 08; fax: +33 1 40 25 86 02. E-mail address:jjmercadier{at}wanadoo.fr


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: In most animal models of chronic hemodynamic overload of the left ventricle (LV) as well as in human end stage heart failure, the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) mRNA levels are decreased in parallel with increased atrial natriuretic peptide (ANP) mRNA levels. The situation in the remote myocardium following myocardial infarction (MI) is unclear.

Aims: (1) To examine SERCA2a mRNA levels in the non-infarcted LV myocardium of rats at the chronic stage of experimental MI and (2) To examine whether a negative linear correlation exists between SERCA2a and ANP mRNA levels in this model.

Methods: Anesthetized adult male Wistar rats underwent left coronary artery ligation or sham operation. Three months later, the rats were divided into three groups: sham-operated rats (sham, n=21), HF-free rats with MI (non-failing (NF)-MI, n=29) and rats with both MI and HF (congestive heart failure (CHF)-MI, n=14). LV remodelling and function were assessed by echocardiography and hemodynamic measurements. SERCA2a and ANP mRNA levels were determined by Northern and dot blot analysis with specific cDNA probes.

Results: LV SERCA2a mRNA levels varied markedly in sham-operated rats (0.9–1.8). Mean ANP mRNA level increased markedly and mean SERCA2a mRNA level decreased moderately in the remote myocardium. In some NF-MI rats, SERCA2a mRNA levels were higher than those in some sham controls. Whereas ANP mRNA levels correlated well with MI severity (r2=0.79, p<0.001), this was not the case for SERCA2a mRNA levels (r2=0.42, p<0.01). We found no negative correlation between ANP and SERCA2a mRNA levels.

Conclusion: SERCA2a gene down-regulation in the non-infarcted myocardium of rats with MI does not correlate with ANP gene up-regulation, suggesting that the two genes are not antithetically regulated.

Key Words: Sarcoplasmic reticulum calcium-ATPase • Atrial natriuretic peptide • Myocardial infarction • Heart failure

Received April 19, 2004; Revised July 14, 2004; Accepted October 14, 2004


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
The contraction and relaxation of cardiac myocytes are governed by rapid changes in the cardiac myocyte intracellular-free Ca2+ concentration ([Ca2+]i), which is itself controlled by Ca2+ release and reuptake by the sarcoplasmic reticulum (SR). It has long been postulated that alterations in SR function could be responsible for both the diastolic and systolic dysfunction seen in heart failure. The SR Ca2+-ATPase (SERCA2a) of cardiac myocytes is the main actor in SR Ca2+ cycling, as it pumps cytosolic Ca2+ back into the SR. This is required for myocyte relaxation and, at least in part, for myocyte contraction, as it reconstitutes the SR Ca2+ stores needed for the next contraction. Because of its importance in Ca2+ cycling, SERCA2a function and expression has been a major research focus during the past two decades [1–3]. Most studies of left ventricular (LV) samples from animal models of LV hypertrophy and failure, and from failing human hearts, agree that SERCA2a expression is reduced during end-stage heart failure (HF) [1–13]. This explains, at least in part, the decreased SR function. In animals, the decrease in SERCA2a expression is most clear-cut in models of pressure-overload-induced LV hypertrophy and failure [1,2,14–22]. In contrast, SERCA2a expression is unchanged in volume-overload-induced LV hypertrophy [23]. Data on SERCA2a gene expression in the non-infarcted LV following MI are less abundant and tend to conflict, with reports of unchanged [24,25], decreased [5,7,9–11,26,27] or even increased expression [28,29]. This could be due to certain particularities of this model of chronic LV hemodynamic overload. Indeed, the remodelling process following myocardial infarction (MI) is more complex than that seen in models of pure pressure or volume overload, as the increase in systolic and diastolic stress on the non-infarcted myocardium depends on scar size and associated LV shape changes [30–33].

In the vast majority of animal models of chronic hemodynamic overload, decreased SERCA2a mRNA levels are paralleled by increased atrial natriuretic peptide (ANP) mRNA levels, a surrogate molecular marker of the degree of myocardial hypertrophy during post-MI LV remodelling [34,35], LV chronic pressure overload [36] and LV volume overload [37]. The concept of an antithetic regulation of the two genes is further supported by the finding by Arai et al. of a strong negative linear correlation between SERCA2a and ANP mRNA levels in LV samples obtained from patients with end stage heart failure at the time of transplantation.

Accordingly, our study had two aims: (1) To examine SERCA2a gene expression levels in the non-infarcted LV of rats in the chronic stage of experimental MI of various sizes, resulting in compensated LV hypertrophy or congestive heart failure. (2) To examine whether a negative linear correlation exists between SERCA2a and ANP mRNA levels in this model of LV chronic hemodynamic overload.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Experimental design
All procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). Male Wistar rats (Charles River, France) weighing 200 g at the time of surgery were used. Left ventricular infarction was obtained by ligating the left coronary artery under anesthesia, as previously described [38,39]. The left descending anterior coronary artery was ligated at variable points after its origin, in order to obtain moderate or large infarcts leading to either LV compensated hypertrophy or failure, respectively. Control rats underwent identical surgery but without coronary artery ligation. Three months later, the rats underwent echocardiography, followed, 1 or 2 days later, by heart catheterization in a subgroup of 31 rats. Echocardiographic and hemodynamic measurements were made in lightly anesthetized (1–2% isoflurane in oxygen), spontaneously breathing animals. Rats were killed after the hemodynamic study and the volume of pleural effusion was carefully measured by needle aspiration and gravimetry. The heart was excised and weighed, and the left ventricle (LV) was dissected free, weighed and stored at –80 °C until use. In 18 consecutive rats with MI, the LV scar was carefully dissected and its surface area was measured using millimeter graph paper. Congestive heart failure (CHF) was defined as the presence of pleural effusion at sacrifice. Accordingly, rats were classified in three groups: sham-operated rats (Sham), rats with non-failing MI (NF-MI), and rats with both MI and congestive heart failure (CHF-MI).

2.2. Echocardiography
Echocardiography was performed with a Toshiba Powervision 6000 SSA 370A device equipped with an 8–14-MHz linear transducer. Data were transferred to a computer for off-line analysis (Ultrasound Image Workstation-300A, Toshiba). The LV was imaged in both parasternal long-axis and short-axis views at the papillary muscle level. The LV ejection fraction (EF) was calculated by using Simpson's modified biplane equation [39,40]. The peak velocity of early mitral flow (E) was measured from the mitral inflow recording as previously described [41]. Peak early diastolic velocity (Ea) and peak systolic velocity (Sa) were measured from pulsed-wave spectral mitral tissue Doppler (TDI) as previously described [42].

2.3. LV hemodynamics
A 3-Fr Mikro-Tip pressure transducer catheter (SPR-524, Millar Instruments) was introduced into the LV through the right carotid artery in 31 consecutive rats (10 Sham and 21 rats with MI). The transducer was connected via a PowerLab/4s unit (ADInstruments) to a computer running MacLab (using Chart 4.1 software). Left ventricular end-diastolic pressure and the maximal rates of LV pressure rise (+dP/dt) and fall (–dP/dt) were measured as previously described [38,39].

2.4. RNA analysis
Total RNA was purified from LV tissue samples according to Chomczinsky and Sacchi [43]. RNA solutions were quantified densitometrically at 260–280 nm. For Northern blot analysis, 10 µg of total RNA was used. For dot blot analysis, 6 µg of RNA was used and serial dilutions (3, 1.5, 0.75, 0,37 µg) were transferred to nylon membranes after denaturalization as described previously [44]. The SERCA2a probe was a 629-bp cDNA complementary to the rat cardiac Ca2+-ATPase mRNA (nucleotides [nt] 1651 to 2279). The ANP probe was a synthetic 710-bp cDNA complementary to the rat ANP mRNA (nt 18 to 718). To check the amount of RNA actually loaded on each lane/dot, we used an oligonucleotide specific for rat 18S RNA as described elsewhere [44]. DNA probes were labeled by random priming (Megaprime labelling kit, Amersham) with [{alpha}32P]-dCTP, and oligonucleotides were labeled with [{gamma}32P]-ATP using T4 kinase. After hybridization, membranes were washed at various final stringencies. The levels of SERCA2a and ANP mRNA, and of 18S RNA were quantified using Instant-Imager.

2.5. Statistical analysis
Values are expressed as means±S.E.M. One-way analysis of variance (ANOVA) followed by Scheffe's F-test was used for group comparisons. Linear regression curves and correlation coefficients were obtained by using the least-squares method (Statview software). p values of <0.05 were considered statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Characteristics of the rats
Sixty-four rats (21 Sham, 29 NF-MI, 14 CHF-MI) were studied 3 months after surgery. Their main characteristics at sacrifice are summarized in Table 1. The scar surface area was larger in CHF-MI rats than in NF-MI rats (p<0.001). The heart weight to body weight ratio was higher in CHF-MI rats than in NF-MI and Sham rats (p<0.001). In addition to the presence of pleural effusion, the decompensated nature of CHF-MI rats relative to NF-MI rats was confirmed by the marked increase in the weight of the part of the heart located hemodynamically upstream of the infarcted LV (the two atria and the right ventricle): the heart weight minus LV weight to body weight ratio was only increased in CHF-MI rats (p<0.001).


View this table:
[in this window]
[in a new window]

  		Table 1 Rat characteristics

 
3.2. Echocardiography
The mean echocardiographic data for the three rat groups are shown in Table 2. Both NF-MI and CHF-MI rats had a dilated LV as compared to Sham rats, as indicated by an increased left ventricular end diastolic diameter in the two former groups. However, LV dilation was much more marked in CHF-MI rats than in NF-MI rats. Global LV systolic function, as assessed by the LV ejection fraction and the peak systolic velocity of the mitral annulus, was markedly altered in CHF-MI rats and, to a lesser extent, in NF-MI rats. LV diastolic function, as assessed by E, Ea and E/Ea, was also markedly altered in CHF-MI rats as compared to Sham rats. In NF-MI rats, however, only E (peak velocity of early mitral inflow) was significantly altered relative to Sham rats, in keeping with the moderate increase in left ventricular end diastolic pressure (LVEDP) in this former group. Using TDI, we found marked alterations in systolic and diastolic functions of the LV inferior wall in CHF-MI rats compared to Sham controls, whereas NF-MI rats only showed systolic dysfunction. As expected, the larger the scar size, the greater the LV systolic and diastolic dysfunction (Fig. 1).


View this table:
[in this window]
[in a new window]

  		Table 2 Echocardiographic data

 


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Correlations between scar surface area and left ventricular hemodynamic parameters; EF, ejection fraction; Sa, peak systolic velocity of the mitral annulus; Ea, early peak diastolic velocity of the mitral annulus; LVEDP, left ventricular end-diastolic pressure; •, Sham-operated rats; {circ}, NF-MI rats; x, CHF-MI rats.

 
3.3. Hemodynamics
The mean hemodynamic data for the three rat groups are shown in Table 3. Data could not be recorded in eight rats, for technical reasons (three Sham, three NF-MI and two CHF-MI). The heart rate (HR) differed slightly among the three rat groups (p<0.05 by ANOVA), but group to group differences were not statistically significant. As expected in this experimental model, mean aortic pressure was lower in CHF-MI rats than in Sham controls, contrary to NF-MI rats (Table 3). In contrast, NF-MI rats had a moderate increase in LVEDP compared to Sham controls, while CHF-MI rats showed a marked increase. Plus and minus dP/dt were markedly decreased in CHF-MI rats compared to Sham controls and NF-MI rats. The latter showed a moderate decrease when +dP/dt was normalized to HR.


View this table:
[in this window]
[in a new window]

  		Table 3 Hemodynamic data

 
3.4. SERCA2a and ANP mRNA expression
Fig. 2 shows typical Northern blots of LV SERCA2a and ANP mRNA and 18S RNA in the three rat groups. As expected, ANP mRNA was undetectable in the LV of sham-operated rats (SH1,2) and accumulated to various degrees in the non-infarcted myocardium of rats with MI. Unexpectedly, SERCA mRNA levels varied markedly among sham-operated rats. In NF-MI rats, the SERCA2a mRNA level was sometimes higher than in Sham controls (see Fig. 2, NF1 vs. SH1), whereas CHF-MI rats (Fig. 2, CHF) had significantly lower levels than both Sham controls (Fig. 2, SH1,2) and NF-MI rats (Fig. 2, NF1,2,3). Interestingly, for a given level of ANP mRNA, SERCA2a mRNA was either increased (NF2) or markedly decreased (CHF) as compared to Sham controls (SH1,2). This suggested that the expression of the two genes is not antithetically regulated in this model of chronic LV overload. The mean values for the three rats groups are shown in Fig. 3. Marked accumulation of ANP mRNA in NF-MI rats, and more markedly in CHF-MI rats, was matched by a moderate decrease in SERCA2a mRNA levels.


Figure 2
View larger version (31K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Autoradiographs of a Northern blot with RNA from sham-operated rats (SH), rats with non-failing MI (NF) and rats with MI and congestive heart failure (CHF), hybridized with probes specific for SERCA2a, ANP and 18S RNA.

 


Figure 3
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Mean (±S.E.M.) left ventricular SERCA2a and ANP mRNA levels. Sham, sham-operated rats; NF-MI, rats with non-failing MI; CHF-MI, rats with MI and congestive heart failure. *p<0.05 vs. Sham; {dagger}p<0.05 vs. NF-MI.

 
Fig. 4A and B shows all LV SERCA2a and ANP mRNA values, plotted as a function of scar size. A strong positive linear correlation was found between scar size and ANP mRNA levels (Fig. 4A, r2=0.79), while a much weaker, negative correlation was found with SERCA2a mRNA (Fig. 4B, r2=0.42). Sham-operated rats showed a very wide range of SERCA2a mRNA values (0.98 to 1.82). The range of values in NF-MI rats was much smaller, and none exceeded the median value of Sham controls. Most values in CHF-MI rats were below the lowest values in the other two rat groups. No negative correlation was found between ANP and SERCA2a mRNA levels (Fig. 4C, r2=0.16). In addition, we found significant negative correlations between remote myocardial systolic and diastolic function (Siw and Eiw) and ANP mRNA levels (ANP/18s=2.88–0.423xSiw, r2=0.65, p<0.001, and ANP/18s=2.05–0.178xEiw, r2=0.39, p<0.01). In contrast, we found no correlation between these parameters and SERCA2a mRNA levels.


Figure 4
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Correlations of scar size with left ventricular ANP (A) and SERCA2a (B) mRNA levels and between SERCA2a and ANP mRNA levels (C). •, Sham-operated rats; {circ}, NF-MI rats; x, CHF-MI rats.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
We examined the SERCA2a and ANP gene expression levels in the non-infarcted rat myocardium 3 months after MI, according to scar size and hemodynamic status. On average, SERCA2a gene expression was down-regulated proportionately to the severity of MI, being more markedly decreased in CHF-MI rats than in NF-MI rats (relative to sham-operated controls). However, individual data revealed more subtle changes. Surprisingly, SERCA2a levels were highly variable in sham-operated rats. Only CHF-MI rats had SERCA2a levels significantly below those in sham controls. Interestingly, in contrast to the situation in humans [6], we failed to find a negative linear correlation between ANP and SERCA2a mRNA levels.

Although decreased SR Ca2+-uptake function is a key feature of LV dysfunction during hypertrophy and failure, there is longstanding controversy over whether LV SERCA2a gene expression is actually decreased during chronic hemodynamic overload (according to the model and stage), and whether humans and other mammalian species differ in this respect. These questions have been best addressed in models of pressure overload. Although we and others initially observed SERCA2a gene down-regulation in the compensated stage of severe LV hypertrophy due to banding of the abdominal aorta [17,22,45], other authors found that values were unchanged and suggested that heart failure was a prerequisite for decreased SERCA2a gene expression during chronic hemodynamic overload, and that down-regulation was thus a consequence rather than a cause of heart failure [19]. It is now generally agreed that SERCA2a mRNA levels, if not protein levels, are decreased during compensated severe LV hypertrophy (LVH), making this a major candidate for mediating the transition from compensated LVH to cardiac failure [20,21]. This view is further supported by a report that adenoviral SERCA2a gene transfer to the LV of rats in transition to heart failure restored the compromised contractile function and delayed heart failure and rat death [46]. In contrast to severe LVH, mild LVH is associated with enhanced SR Ca2+ transport, a process known since 1980 [47]. Arai et al. [18] showed in 1996 that SERCA2a gene expression is up-regulated in mild but down-regulated in severe pressure-overload-induced LVH. This could explain why some NF-MI rats in our study had LV SERCA2a mRNA levels higher than those in some sham-operated rats. In contrast to pressure overload, SERCA2a mRNA levels are reported to be unchanged in volume-overload-induced LV hypertrophy [16,23], in good agreement with the variable decrease in {alpha}-MHC gene expression in rats with LVH secondary to aorto-caval fistula [48].

Relatively little is known about post-MI SERCA2a gene regulation in the non-infarcted myocardium. Three months post-MI, Yoshiyama et al. [24] found decreased SERCA2a mRNA levels only in the myocardial region adjacent to the infarct, whereas β-MHC, alpha-skeletal actin and Na+–Ca2+ exchanger mRNA levels were increased in remote regions, suggesting that SERCA2a gene down-regulation and expression of the hypertrophy gene program are not necessarily linked. Yue et al. [25] found that SERCA2a expression in rats was not altered 1, 7 and 42 days post-MI, despite a comparable degree of cellular hypertrophy and more severe hemodynamic decompensation than in rats with pressure-overload-induced heart failure. Gupta et al. [28] reported a decrease in SERCA2a mRNA but no decrease in SERCA2a protein in animals with intact myocyte contractile function, 6 weeks post-MI. Zhang et al. [26] found a 23% reduction in SERCA2a expression, correlating with a 19% prolongation of the Ca2+ transient, 3 weeks after moderate MI, while Kim et al. [27] found a 30% decrease in SERCA2a protein in myocytes adjacent to the infarction scar compared with remote myocardium, 8 weeks post-MI. The reasons for these conflicting results are unclear, but may be related to the complexity of the mechanical overload of the non-infarcted myocardium; indeed, components of pressure and volume overload may have, if not totally opposite, at least different modulatory effects on LV SERCA2a gene expression. The timing of measurements after MI, and differences in HF severity, might also account for some of discrepancies.

Intriguingly, SERCA2a mRNA values were highly variable in our sham-operated rats. We checked that this variability was not due to sampling of different areas of the left ventricle (data not shown). The fact that the rats we used were not inbreed might have played an important part in this variability. SERCA2a gene expression is highly sensitive to thyroid status, increasing with hyperthyroidism and decreasing with hypothyroidism [22], but it is very unlikely that our sham-operated rats differed in this respect. In contrast, a role of hypothyroidism cannot be ruled out in rats with MI, and especially in those with associated heart failure, as severe disease condition is often associated with mild hypothyroidism [49,50].

The variability of SERCA2a mRNA levels was much less marked in NF-MI rats than in sham-operated rats (see Fig. 4B). This indicates that LV hypertrophy tends to homogenize values at the lower level of the control range, although it is conceivable that rats with the highest LV SERCA2a levels died of severe ventricular arrhythmias during the acute phase of MI, as reported in transgenic rats with LV SERCA2a overexpression [39]. Furthermore, all CHF-MI rats but one had SERCA2a mRNA levels below the lowest value observed in sham-operated controls, suggesting the existence of two regulatory processes, one associated with LV hypertrophy and the other with heart failure. The triggers of these regulatory processes are elusive, especially regarding the transition from SERCA2a overexpression in mild LVH to decreased SERCA2a expression in more severe LVH. Several regulatory regions have recently been identified in the SERCA2a promoter, including a transcription activation site located between two transcription inhibition sites [16,51]. Severe pressure-overload-induced LVH is required to produce a significant decrease in SERCA2a promoter activity [16]. More recently, the transcription factors Sp1 and Sp3 were shown to be involved in this process [52,53], Sp1 gene up-regulation correlating with SERCA2a gene down-regulation [52]. A subtle balance between activators and inhibitors of SERCA2a gene transcription, specific to individual MI rats in our study, might explain the variability of SERCA2a mRNA levels, especially in NF-MI rats, although post-transcriptional regulatory factors cannot be excluded. Numerous factors might explain the more homogeneous SERCA2a down-regulation during heart failure; these could include the increase in diastolic and systolic wall stress associated with LV chamber dilation and increase in sphericity, and the various neuro-hormonal changes associated with HF.

The respective up-regulation and down-regulation of the ANP and SERCA2a genes during heart failure have led to an intensive search for a negative correlation between the corresponding mRNA levels. Such a correlation was found by Arai et al. [6] in LV tissue samples taken from patients with dilated cardiomyopathy or ischemic heart disease. We found no such correlation. There are many reasons for such a discrepancy. First, Arai. et al. studied LV samples gathered from patients with end stage heart failure at the time of heart transplantation. It is likely that the long lasting LV hemodynamic overload in these patients and the resulting increase in LV size and sphericity, resulted in a more homogeneous study population than that of the rats of the present study which also includes Sham controls and rats with NF-MI. It is likely that the variability of SERCA2a mRNA levels in Sham controls and the high proportion in our study of rats with NF-MI with both high ANP and SERCA2a mRNA levels also played a role.

In conclusion, during the chronic phase of myocardial infarction in rats, SERCA2a mRNA levels are consistently reduced only in animals that progress to heart failure, while levels in other animals lie within the bottom half of control values. While ANP gene up-regulation correlates with MI severity, this is not the case of SERCA2a gene down-regulation, suggesting that SERCA2a gene expression is subject to complex regulation following myocardial infarction.


   Acknowledgments
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This work was supported in part by grants from Fondation de France and Fondation Lefoulon-Delalande. The authors are grateful to D. Young for his help in restyling the manuscript.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
1 Current address: Laboratoire de Préconditionnement et Remodelage du Myocarde, Angers, France. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

  1. Arai M., Matsui H., Periasamy M. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ. Res. (1994) 74(4):555–564.[Free Full Text]
  2. Houser S.R., Piacentino V. III, Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J. Mol. Cell. Cardiol. (2000) 32(9):1595–1607.[CrossRef][Web of Science][Medline]
  3. Periasamy M., Huke S. SERCA pump level is a critical determinant of Ca(2+) homeostasis and cardiac contractility. J. Mol. Cell. Cardiol. (2001) 33(6):1053–1063.[CrossRef][Web of Science][Medline]
  4. Mercadier J.J., Lompre A.M., Duc P., Boheler K.R., Fraysse J.B., Wisnewsky C., et al. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J. Clin. Invest. (1990) 85(1):305–309.[Web of Science][Medline]
  5. Gwathmey J.K., Warren S.E., Briggs G.M., Copelas L., Feldman M.D., Phillips P.J., et al. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J. Clin. Invest. (1991) 87(3):1023–1031.[Web of Science][Medline]
  6. Arai M., Alpert N.R., MacLennan D.H., Barton P., Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ. Res. (1993) 72(2):463–469.[Abstract/Free Full Text]
  7. Hasenfuss G., Reinecke H., Studer R., Meyer M., Pieske B., Holtz J., et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ. Res. (1994) 75(3):434–442.[Abstract/Free Full Text]
  8. Schwinger R.H., Bohm M., Schmidt U., Karczewski P., Bavendiek U., Flesch M., et al. Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation (1995) 92(11):3220–3228.[Abstract/Free Full Text]
  9. Meyer M., Schillinger W., Pieske B., Holubarsch C., Heilmann C., Posival H., et al. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation (1995) 92(4):778–784.[Abstract/Free Full Text]
  10. Linck B., Boknik P., Eschenhagen T., Muller F.U., Neumann J., Nose M., et al. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts. Cardiovasc. Res. (1996) 31(4):625–632.[Abstract/Free Full Text]
  11. Arai M., Tomaru K., Takizawa T., Sekiguchi K., Yokoyama T., Suzuki T., et al. Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits. J. Mol. Cell. Cardiol. (1998) 30(2):243–254.[CrossRef][Web of Science][Medline]
  12. Schmidt U., Hajjar R.J., Helm P.A., Kim C.S., Doye A.A., Gwathmey J.K. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J. Mol. Cell. Cardiol. (1998) 30(10):1929–1937.[CrossRef][Web of Science][Medline]
  13. Hasenfuss G., Schillinger W., Lehnart S.E., Preuss M., Pieske B., Maier L.S., et al. Relationship between Na+–Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation (1999) 99(5):641–648.[Abstract/Free Full Text]
  14. Levitsky D., de la Bastie D., Schwartz K., Lompre A.M. Ca(2+)-ATPase and function of sarcoplasmic reticulum during cardiac hypertrophy. Am. J. Physiol. (1991) 261(4 Suppl.):23–26.[Web of Science][Medline]
  15. Matsui H., MacLennan D.H., Alpert N.R., Periasamy M. Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbit. Am. J. Physiol. (1995) 268(1 Pt. 1):C252–C258.[Web of Science][Medline]
  16. Aoyagi T., Yonekura K., Eto Y., Matsumoto A., Yokoyama I., Sugiura S., et al. The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J. Mol. Cell. Cardiol. (1999) 31(4):919–926.[CrossRef][Web of Science][Medline]
  17. de la Bastie D., Levitsky D., Rappaport L., Mercadier J.J., Marotte F., Wisnewsky C., et al. Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ. Res. (1990) 66(2):554–564.[Abstract/Free Full Text]
  18. Arai M., Suzuki T., Nagai R. Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload. J. Mol. Cell. Cardiol. (1996) 28(8):1583–1590.[CrossRef][Web of Science][Medline]
  19. Feldman A.M., Weinberg E.O., Ray P.E., Lorell B.H. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ. Res. (1993) 73(1):184–192.[Abstract]
  20. Kiss E., Ball N.A., Kranias E.G., Walsh R.A. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. Circ. Res. (1995) 77(4):759–764.[Abstract/Free Full Text]
  21. Qi M., Shannon T.R., Euler D.E., Bers D.M., Samarel A.M. Downregulation of sarcoplasmic reticulum Ca(2+)-ATPase during progression of left ventricular hypertrophy. Am. J. Physiol. (1997) 272(5 Pt. 2):H2416–H2424.[Web of Science][Medline]
  22. Nagai R., Zarain-Herzberg A., Brandl C.J., Fujii J., Tada M., MacLennan D.H., et al. Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proc. Natl. Acad. Sci. U. S. A. (1989) 86(8):2966–2970.[Abstract/Free Full Text]
  23. Calderone A., Takahashi N., Izzo N.J. Jr., Thaik C.M., Colucci W.S. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation (1995) 92(9):2385–2390.[Abstract/Free Full Text]
  24. Yoshiyama M., Takeuchi K., Hanatani A., Kim S., Omura T., Toda I., et al. Differences in expression of sarcoplasmic reticulum Ca2+-ATPase and Na+–Ca2+ exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction. J. Mol. Cell. Cardiol. (1997) 29(1):255–264.[CrossRef][Web of Science][Medline]
  25. Yue P., Long C.S., Austin R., Chang K.C., Simpson P.C., Massie B.M. Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. J. Mol. Cell. Cardiol. (1998) 30(8):1615–1630.[CrossRef][Web of Science][Medline]
  26. Zhang X.Q., Ng Y.C., Moore R.L., Musch T.I., Cheung J.Y. In situ SR function in postinfarction myocytes. J. Appl. Physiol. (1999) 87(6):2143–2150.[Abstract/Free Full Text]
  27. Kim Y.K., Kim S.J., Kramer C.M., Yatani A., Takagi G., Mankad S., et al. Altered excitation–contraction coupling in myocytes from remodeled myocardium after chronic myocardial infarction. J. Mol. Cell. Cardiol. (2002) 34(1):63–73.[CrossRef][Web of Science][Medline]
  28. Gupta S., Prahash A.J., Anand I.S. Myocyte contractile function is intact in the post-infarct remodeled rat heart despite molecular alterations. Cardiovasc. Res. (2000) 48(1):77–88.[Abstract/Free Full Text]
  29. Pennock G.D., Spooner P.H., Summers C.E., Litwin S.E. Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA). J. Mol. Cell. Cardiol. (2000) 32(11):1939–1953.[CrossRef][Web of Science][Medline]
  30. Pfeffer M.A., Pfeffer J.M., Fishbein M.C., Fletcher P.J., Spadaro J., Kloner R.A., et al. Myocardial infarct size and ventricular function in rats. Circ. Res. (1979) 44(4):503–512.[Abstract/Free Full Text]
  31. Picard M.H., Wilkins G.T., Ray P.A., Weyman A.E. Natural history of left ventricular size and function after acute myocardial infarction. Assessment and prediction by echocardiographic endocardial surface mapping. Circulation (1990) 82(2):484–494.[Abstract/Free Full Text]
  32. Pfeffer M.A., Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation (1990) 81(4):1161–1172.[Abstract/Free Full Text]
  33. Michel J.B., Nicolletti A., Arnal J.F. Left ventricular remodelling following experimental myocardial infarction. Eur. Heart J. (1995) 16(Suppl. I):49–57.[Abstract/Free Full Text]
  34. Michel J.B., Mercadier J.J., Galen F.X., Urbain R., Dussaule J.C., Philippe M., et al. Urinary cyclic guanosine monophosphate as an indicator of experimental congestive heart failure in rats. Cardiovasc. Res. (1990) 24(11):946–952.[Abstract/Free Full Text]
  35. Michel J.B., Lattion A.L., Salzmann J.L., Cerol M.L., Philippe M., Camilleri J.P., et al. Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ. Res. (1988) 62(4):641–650.[Abstract/Free Full Text]
  36. Mercadier J.J., Samuel J.L., Michel J.B., Zongazo M.A., de la Bastie D., Lompre A.M., et al. Atrial natriuretic factor gene expression in rat ventricle during experimental hypertension. Am. J. Physiol. (1989) 257(3 Pt. 2):H979–H987.[Web of Science][Medline]
  37. Lattion A.L., Michel J.B., Arnauld E., Corvol P., Soubrier F. Myocardial recruitment during ANF mRNA increase with volume overload in the rat. Am. J. Physiol. (1986) 251(5 Pt. 2):H890–H896.[Web of Science][Medline]
  38. Prunier F., Gaertner R., Louedec L., Michel J.B., Mercadier J.J., Escoubet B. Doppler echocardiographic estimation of left ventricular end-diastolic pressure after MI in rats. Am. J. Physiol. Heart Circ. Physiol. (2002) 283(1):H346–H352.[Abstract/Free Full Text]
  39. Chen Y., Escoubet B., Prunier F., Amour J., Simonides W.S., Vivien B., et al. Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation (2004).
  40. Schiller N.B., Shah P.M., Crawford M., De Maria A., Devereux R., Feigenbaum H., et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J. Am. Soc. Echocardiogr. (1989) 2(5):358–367.[Medline]
  41. Mulvagh S., Quinones M.A., Kleiman N.S., Cheirif J., Zoghbi W.A. Estimation of left ventricular end-diastolic pressure from Doppler transmitral flow velocity in cardiac patients independent of systolic performance. J. Am. Coll. Cardiol. (1992) 20(1):112–119.[Abstract]
  42. Nagueh S.F., Middleton K.J., Kopelen H.A., Zoghbi W.A., Quinones M.A. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J. Am. Coll. Cardiol. (1997) 30(6):1527–1533.[Abstract]
  43. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal. Biochem. (1987) 162(1):156–159.[Web of Science][Medline]
  44. Mercadier J.J., Dubus I. Assay of atrial natriuretic factor messenger ribonuceic acid. In: Methods in neurosciences—Conn P.M., ed. (1991) vol. 5. San Diego, CA: Academic Press. 22–34.
  45. Komuro I., Kurabayashi M., Shibazaki Y., Takaku F., Yazaki Y. 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. (1989) 83(4):1102–1108.[Web of Science][Medline]
  46. del Monte F., Williams E., Lebeche D., Schmidt U., Rosenzweig A., Gwathmey J.K., et al. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation (2001) 104(12):1424–1429.[Abstract/Free Full Text]
  47. Limas C.J., Spier S.S., Kahlon J. Enhanced calcium transport by sarcoplasmic reticulum in mild cardiac hypertrophy. J. Mol. Cell. Cardiol. (1980) 12(10):1103–1116.[CrossRef][Web of Science][Medline]
  48. Mercadier J.J., Lompre A.M., Wisnewsky C., Samuel J.L., Bercovici J., Swynghedauw B., et al. Myosin isoenzyme changes in several models of rat cardiac hypertrophy. Circ. Res. (1981) 49(2):525–532.[Abstract/Free Full Text]
  49. Custro N., Scafidi V., Costanzo G., Notarbartolo A. Prospective study on thyroid function anomalies in severely ill patients. Ann. Ital. Med. Int. (1992) 7(1):13–18.[Medline]
  50. Fliers E., Alkemade A., Wiersinga W.M. The hypothalamic-pituitary-thyroid axis in critical illness. Best Pract. Res. Clin. Endocrinol. Metab. (2001) 15(4):453–464.[CrossRef][Medline]
  51. Takizawa T., Arai M., Yoguchi A., Tomaru K., Kurabayashi M., Nagai R. Transcription of the SERCA2 gene is decreased in pressure-overloaded hearts: a study using in vivo direct gene transfer into living myocardium. J. Mol. Cell. Cardiol. (1999) 31(12):2167–2174.[CrossRef][Web of Science][Medline]
  52. Takizawa T., Arai M., Tomaru K., Koitabashi N., Baker D.L., Periasamy M., et al. Transcription factor Sp1 regulates SERCA2 gene expression in pressure-overloaded hearts: a study using in vivo direct gene transfer into living myocardium. J. Mol. Cell. Cardiol. (2003) 35(7):777–783.[CrossRef][Web of Science][Medline]
  53. Brady M., Koban M.U., Dellow K.A., Yacoub M., Boheler K.R., Fuller S.J. Sp1 and Sp3 transcription factors are required for trans-activation of the human SERCA2 promoter in cardiomyocytes. Cardiovasc. Res. (2003) 60(2):347–354.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur J Heart FailHome page
X.-Y. Zhao, S.-J. Hu, J. Li, Y. Mou, K. Bian, J. Sun, and Z.-H. Zhu
rAAV-asPLB transfer attenuates abnormal sarcoplasmic reticulum Ca2+-ATPase activity and cardiac dysfunction in rats with myocardial infarction
Eur J Heart Fail, January 1, 2008; 10(1): 47 - 54.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Prunier, F.
Right arrow Articles by Mercadier, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Prunier, F.
Right arrow Articles by Mercadier, J.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?