Skip Navigation

European Journal of Heart Failure 2004 6(7):845-851; doi:10.1016/j.ejheart.2004.01.014
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 Philipp, S.
Right arrow Articles by Willenbrock, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Philipp, S.
Right arrow Articles by Willenbrock, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2004 European Society of Cardiology

Regulation of caspase 3 and Fas in pressure overload-induced left ventricular dysfunction

Sebastian Philippa, Ines Pagela, Klaus Höhnela, Jens Lutzb, Jens Buttgereita, Thomas Langenickela, Pavel Hametc, Rainer Dietza and Roland Willenbrocka,d,*

a Franz-Volhard-Clinic at the Max Delbrueck Center for Molecular Medicine, Helios-Kliniken Berlin, University Hospital Charité Berlin, Germany
b Department of Nephrology, University Clinic Essen Germany
c Centre de Recherché du Centre Hospitalier de l'Université de Montreal Campus Hôtel-Dieu, Montreal, Canada
d St. Elisabeth Hospital Mauerstr. 5, 06110 Halle/Salle, Germany

* Corresponding author. Tel.: +49-345-213-4231; Fax: +49-345-213-4232 E-mail address: willenbrock{at}krankenhaus-halle-saale.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The presence of apoptotic cell death in cardiac myocytes is now well established and the contribution of apoptosis for the development of heart failure has been suggested. However, the mechanism responsible for the induction of apoptosis remains unclear. The present study was designed to investigate the involvement of Fas and caspase 3 in the transition from pressure overload-induced left ventricular hypertrophy (LVH) to left ventricular dysfunction (LVD).

Methods: Pressure overload induced LVH (10 days) and LVD (30 days) were induced by thoracic aortic banding. Changes in apoptosis-related genes were studied in rats with thoracic aortic banding. After 10 and 30 days, cardiac Fas mRNA expression was measured by RT-PCR. The mRNA expression of caspase 3 was detected by RNase protection assay. The activity of caspase 3 was measured by fluorometric assay. Protein levels of caspase 3 were measured by Western blot.

Results: Rats with aortic banding had increased heart/body weight ratios after 10 and 30 days, compared to controls. Central venous pressure and lung weights were increased, left ventricular contractility was significantly impaired only in rats after 30 days of aortic banding, indicating LVD. Caspase 3 mRNA expression (7.1±0.1 vs. 2.8±0.4, P<0.05), caspase 3 activity (1418±181 vs. 849±154 AU, P<0.05) as well as caspase 3 protein levels were increased in rats with LVD but not with LVH. Similarly, Fas mRNA was increased in rats with LVD.

Conclusions: The activation of Fas and caspase 3 only after 30 days of aortic banding suggests that induction of these pathways may be involved in pressure overload-induced LVD.

Key Words: Caspase • Fas • Left ventricular dysfunction • Left ventricular hypertrophy • Heart • Rat

Received January 16, 2003; Revised January 5, 2004; Accepted January 19, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The presence of apoptotic cell death in cardiac myocytes is now well established in vivo and in vitro [1,2] and the contribution of apoptosis for the development of heart failure has been suggested [3]. However, the mechanism responsible for the induction of apoptosis is still unclear. The present study was designed to investigate the involvement of Fas and caspase 3 in pressure overload-induced left ventricular hypertrophy (LVH) and dysfunction (LVD).

Apoptosis has been associated with the development of myocardial hypertrophy in spontaneously hypertensive rats [1], in the aging rat myocardium [4] and was induced within a few days after pressure overload in rats [5]. Apoptosis occurs also in overt human heart failure [2]. It had been shown recently that Fas receptor signaling is necessary for cardiac hypertrophy in response to the biomechanical stress of pressure overload [6,7]. No data are yet available on the regulation of Fas genes and of caspase 3 in the transition from LVH to LVD in rats with chronic pressure overload.

Cardiac hypertrophy occurs in response to the biomechanical stress of pressure overload, which is often caused by arterial hypertension. This adaptive growth is initially of compensatory nature, but sustained hypertrophy may undergo a transition to heart failure, a leading cause of mortality in developed countries [8]. Apoptosis, leading to myocyte loss, is thought to contribute to experimental and clinical heart failure [2,9]. Activation of the Fas/APO-1 receptor by Fas ligand represents a classical death signal causing apoptosis via activation of the caspase cascade in many cell types [10]. Caspases are specialized cysteine-dependent, aspartate-directed proteases, which cleave major structural elements of the cytoplasm and nucleus in the cells [11]. The activated caspase 3 is capable of autocatalysis as well as cleaving and activating other members of the caspase family, leading to rapid and irreversible apoptosis [12]. Activated caspase 3 will cleave and activate the 45 kd subunit of the DNA fragmentation factor, which in turn leads to the degradation of DNA into nucleosomal fragments [13], a hallmark of apoptosis [14]. Further caspase 3 activation directly targets three components of myofilaments, namely {alpha}-actin, {alpha}-actinin and cardiac troponin T. The cleavage of these proteins by caspase 3 has direct functional effects on myofilament activation and contractile function [15].

Therefore, we investigated the regulation of caspase 3 in the transition from chronic pressure overload-induced left ventricular hypertrophy (LVH) to left ventricular dysfunction (LVD).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Aortic banding
Male Sprague–Dawley rats (body weight 100–110 g) were anaesthetized by chloral hydrate (400 µg/kg), intubated and artificially ventilated. After thoracotomy, a tantalum clip (internal diameter 0.51 mm) was placed around the ascending aorta. Perioperative mortality was 10%. After 10 and 30 days hemodynamic measurements were performed, the hearts were removed; ventricles were dissected free, weighed and kept in liquid nitrogen until further analysis. The investigation conforms with the guide for the care and use of laboratory animals published by the US National Institutes of Health and was approved by the local committee.

2.2. Determination of cardiac function
The animals were intubated and artificially ventilated under chloral hydrate anesthesia, 10 and 30 days after aortic banding. A PE 50-catheter was inserted through the right jugular vein into the superior vena cava. Arterial blood pressure was measured directly via the left carotid artery. Left ventricular hemodynamics were measured after thoracotomy by inserting a PE 50-catheter with a 14 g needle through the free left ventricular wall into the left ventricle. Due to this, we were not able to use a high fidelity catheter. Pressures were registered with a Statham transducer (P23XL) and a Gould amplifier (AMP 4600). Left ventricular contractility was obtained from the ventricular pressure curves.

2.3. Determination of ANP plasma concentration
Blood samples of atrial natriuretic peptide (ANP) were withdrawn from the aorta in Na-EDTA preloaded and prechilled tubes. The blood was centrifuged at 4 °C at 2000xg for 10 min immediately after withdrawal, and the plasma was maintained at –80 °C until extraction. ANP plasma samples were extracted using C18 Sep-Pak columns that had been equilibrated with acetonitrile and ammonium acetate (0.2%, pH 4.0). After plasma loading, the columns were washed with ammonium acetate, and ANP were eluted with acetonitrile–ammonium-acetate. The recovery of the peptide was ca. 80% and was taken into account when plasma values were calculated. Samples were then measured by radioimmunoassay.

2.4. Measurement of Fas mRNA
The expression of Fas mRNA was measured by RT-PCR. RNA was isolated from each left ventricle by the guanidinium thiocyanate and phenol/chloroform method [16]. The concentration of isolated RNA was determined spectrophotometrically at 260-nm wavelength. Reverse transcription took place in the presence of 1xfirst strand buffer, 0.5 mM of each deoxyribonucleoside triphosphates (dNTP), 0.4 U/µl RNase inhibitor, 3 ng/µl of oligo (dt)16 primers and 0.5 U/µl Moloney murine leukemia virus reverse transcriptase. Reaction mixtures were first incubated in the absence of enzymes, nucleotides and buffer at 65 °C for 10 min and cooled down to room temperature. Reverse transcriptase, RNase inhibitor, buffer, nucleotides and water were then added. Reverse transcription reaction mixtures were incubated at 37 °C for 60 min and reactions were stopped by heating at 95 °C for 5 min. The specific primers used are: forward: 5'-ATG TTT CAG CTC TTC CAC-3', reverse: 5'-AGA GAG AGC TCA GAT ACG-3. Subsequent PCR amplifications were performed in a volume of 100 µl, which contained 10 µl of cDNA, 10 mM Tris–HCl, 1.5 mM MgCl2, 50 mM KCL, 0.1% Triton X-100, 0.2 mM of dNTP and 0.025U/µl PrimeZyme thermo stable DNA polymerase. The mixture was heated initially for 5 min at 94 °C followed by 35 cycles (30 s at 60 °C, 1 min at 72 °C, 45 s at 94 °C). A final extension was performed at 72 °C for 10 min and PCR was stopped by incubation at 4 °C. The specific PCR products for Fas were run in a 1.2% agarose gel and their optical density was measured by NIH-Image software and a semiquantative analysis was performed.

2.5. mRNA expression of apoptosis related genes
After isolation of total cellular RNA as previously described [17], the mRNA levels of Fas, FasL, bcl-2, bax and caspase 1, 2 and 3 were analyzed by ribonuclease protection assay. Specific anti-sense riboprobes (Pharmingen, San Diego, CA) were prepared by in-vitro transcription with the incorporation of 32P-UTP according to the manufacturers protocol using the RiboQuantTM Kit (RiboQuantTM Multi-Probe Ribonuclease Protection Assay System, Pharmingen, San Diego, CA) [18]. Total RNA samples were hybridized according to the manufacturers protocol with their respective rat anti-sense riboprobes, followed by RNA- and RNase digestion and separation on a 6% polyacrylamide gel. Dried polyacrylamide gels were scanned on a Fuji-BAS phosphor imager (Fuji, Duesseldorf, Germany). The blot was digitized and the density of bands was measured. Data represent the ratio between specific mRNA and the housekeeping gene glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) mRNA.

2.6. Caspase 3 activity
In addition to determination of caspase mRNA, Caspase 3 activity was measured optofluorometrically [19]. The assay is based on the cleavage of the synthetic tetrapeptide substrate Ac-DEVD-AMC (N-acetyl-Asp-Glu-Val-Asp-(7-amino-4-methylcoumarin)) by active caspase 3. The substrate is cleaved between Ac-DEVD and AMC, releasing the fluorogenic AMC, which is then detected by spectrofluorometry. In the presence of caspase 3, fluorogenic AMC is released from Ac-DEVD-AMC, reflecting the activity of caspase 3. One hundred milligrams of tissue were homogenized, washed with phosphate-buffered saline and lysed in 0.5 ml of Buffer 1 containing 5 mM DTT (Dithiothreitol), 1 mM PMSF, 20 µg/ml Leupeptin, 10 µl/ml Pepstatin A and 10 µg/ml Aprotonin. After centrifugation (10 000xg, 4 °C, 10 min), the pellet was resuspended in Buffer 2 containing 50 mM Tris–HCl (pH 7.4), 5 mM MgCl2, 1 mM EGTA, 0.1% CHAPS (3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate) and 1 mM DTT. Protein concentration was measured using a Bradford assay. After incubation of 100 µl of suspension, containing approximately 50 µg of proteins, with 10 mM Ac-DEVD-CHO solution (in DMSO) for 30 min in 37 °C, 10 mM Ac-DEVD-AMC-suspension (in DMSO) was added in a 96 well plate. Fluorescence was measured at an excitation wavelength of 365 nm and emission wavelength of 465 nm with fluorometric reader (Microplate Fluorescence Reader FL 500, Biolite F1, Labtech Int. Ltd.). Antibodies were obtained from Calbiochem.

2.7. Western blots
Protein was extracted from frozen tissue in a cell extraction buffer (Cell Signaling Technology) containing 50 mM Pipes/NaOH (pH 6.5), 2 mM EDTA, 0.1% CHAPS, 5 mM DTT, 20 µg leupeptin, 10 µg/ml pepstatin, 10 µg/ml aprotinin and 1 mM PMSF according to the manufactures protocol. Protein concentration was determined using the Bradford assay (Bio-Rad). Total protein (80 µg) was separated by electrophoresis on a 12% polyacrylamide gel and blotted onto a nitrocellulose membrane. Membranes were incubated with a specific primary antibody to caspase 3 (Cell Signaling Technology) at a dilution of 1:1000 overnight and with HRP-conjugated goat-antirabbit secondary antibody (1:15 000, Sigma). Signals were revealed with chemiluminescence using the ECL-detection system (Amersham). Quantification of the signals was performed using NIH image. Two bands of caspase 3 were detected, the large one (32 kDa) representing the proenzyme and the smaller one (20 kDa) representing the activated (cleaved) enzyme caspase 3.

2.8. Statistical analysis
All results are expressed as means±S.E. of the mean. Comparisons between groups were performed with a paired Student's t-test. P values <0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Weight, hemodynamic and humoral assessment
The model of aortic banding is characterized by left ventricular hypertrophy, as indicated by increased absolute and relative heart weights after 10 and 30 days (Table 1). Arterial blood pressure was significantly lower after 10 days in the group with aortic banding whereas no difference was observed after 30 days between both groups (Table 2). At both time points, left ventricular end-diastolic pressures were elevated. The lung weights increased only after 30 days, indicating pulmonary congestion, a typical feature of severe LVD. Only after 30 days of aortic banding, central venous pressure was elevated and left ventricular contractility was reduced, compared to sham-operated rats, confirming the presence of left ventricular dysfunction.


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

  		Table 1 Body and organ weights after thoracic aortic banding

 


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

  		Table 2 Hemodynamic parameters after thoracic aortic banding

 
Plasma concentrations of atrial natriuretic peptide, a humoral marker of left ventricular dysfunction, were markedly raised in rats with aortic banding, compared to sham-operated animals (1826±373 vs. 708±173 fmol/l, P<0.05) after 30 days.

3.2. Expression of Fas mRNA
We determined whether rats with LVD due to aortic banding led to an enhanced induction of Fas gene expression. The cardiac expression of Fas mRNA, as detected by ribonuclease protection assay, appeared higher in rats with aortic banding, but the difference did not reach statistical significance. Further, we were able to detect a non-significant increase in FasL mRNA. We further performed a RT-PCR. Fas mRNA was significantly increased after 30 days of aortic banding compared to controls (144%) whereas no significant difference in the expression of Fas mRNA was seen after 10 days (Fig. 1).


Figure 1
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Fas mRNA was detected by RT-PCR in left ventricles of rats after 10 and 30 days of aortic banding (n of each group=10). Sham-operated animals are set as 100%. Rats with LVH had no significant increase in Fas mRNA whereas rats with LVD showed a 144% increase in Fas mRNA (a). Typical gel electrophoresis of the PCR products are shown for two sham-operated rats and five animals after 30 days of aortic banding (b). Thymus mRNA served as positive control. ***=P<0.001 vs. sham.

 
3.3. mRNA expression of apoptose related genes
We did not observe any significant changes after chronic aortic banding in the mRNA expression levels (normalized to mRNA of GAPDH) of bax, bcl-2, and caspase 1, as shown in Fig. 2. Caspase 2 showed a non-significant tendency towards higher values (P=0.16).


Figure 2
View larger version (52K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 The mRNA expression of caspase 1, 2 and 3, normalized to GAPDH mRNA, after 30 days of aortic banding are shown in (a). Caspase 3 mRNA was significantly increased, while none of the other apoptosis related gene was significantly changed. A sample blot is shown in (b) (banding n=9, sham n=7).

 
3.4. Upregulation of mRNA expression of caspase 3
We determined the regulation of caspase 3 mRNA after 30 days of aortic banding. As shown in Fig. 2, caspase 3 mRNA was almost tripled (P<0.05) after 30 days of aortic banding. We then evaluated whether the enhanced cardiac expression of caspase 3 mRNA was reflected by increased caspase activity.

3.5. Caspase 3 activity
Activation of the caspase cascade is an irreversible step in apoptotic DNA degradation. However, no data on the measurement of caspase activity in LVD are available. Using DEVD-AMC as substrate for caspase 3, no significant change was observed after 10 days of aortic banding (Fig. 3a). After 30 days, a significantly increased activation of caspase 3 was detected in rats with aortic banding (1418±181 vs. 849±154 AU, P<0.05). The caspase 3 activity correlated significantly with the left ventricular end-diastolic pressure (r=0.702, P<0.05), with the plasma concentrations of ANP (r=0.719, P<0.01), the central venous pressure (r=0.660, P<0.05) and lung weight (r=0.539, P<0.05) in rats after 30 days of aortic banding, suggesting an association between apoptosis and LVD.


Figure 3
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 The activity of caspase 3 in left ventricles from rats after 10 and 30 days of aortic banding or sham-operation is shown in (a) (n=9 for each control and banding 10 days; n=10 for each control and banding 30 days). The quantification of caspase 3 protein levels (b, upper part) demonstrates a three-fold increase after 30 days of banding. A typical Western Blot demonstrates the induction of caspase 3 full-length protein and of the cleaved form (b, lower part, n=12 for both groups). *=P<0.05, **=P<0.01 vs. sham.

 
3.6. Protein levels of caspase 3
We determined protein levels of caspase 3 by Western blot (Fig. 3b). Caspase 3 was increased in rats after 30 days of aortic banding by 295±56% (P<0.05). In addition, the concentration of the activated form of caspase 3 was increased after 30 days of banding, further confirming the role of caspase 3 in this model of LVD. There was no change in protein levels of caspase 3 after 10 days (data not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Left ventricular hypertrophy is an adaptive cardiac response to the imposition of pressure overload to the heart [20]. The initial benefits of cardiac hypertrophy, such as normalization of wall stress and preservation of systolic force generation, may be offset during the late stages of chronic hemodynamic overload due to progressive cell loss, which may lead to deterioration of cardiac function [21,22]. Despite several investigations that have identified a variety of factors that initiate apoptosis in hypertrophied hearts little is known about the activated apoptotic pathways in response to hypertrophic stimuli in hearts that had developed LVD [1,23–25].

The present study was performed to examine the regulation of caspase 3, a key protease in the apoptotic pathway. Since Condorelli et al. [3] demonstrated an increase in apoptotic cardiomyocytes and a change in proapoptotic and antiapoptotic genes bcl-2 and bax in the transition from LVH to LVD, we focused on the regulation of caspase 3 and Fas. The experimental model of ascending thoracic aortic banding in rats was employed for induction of LVH and LVD [26]. Left ventricular weight was increased by over 50% after 30 days of aortic banding. At that time plasma ANP levels were markedly elevated, lung weight was increased, end-diastolic pressure and central venous pressure were elevated and left ventricular contractility was reduced-all signs of left ventricular dysfunction. The development of experimental LVD after a period of pressure overload and cardiac hypertrophy is similar as it has been described for human hypertension and aortic stenosis, over a compressed time span [20].

No induction of caspase 3 mRNA, protein concentration nor activity was observed in the model of LVH. After prolonged exposure to pressure overload, when LVH had progressed into LVD, the presence of upregulated Fas mRNA, induced caspase 3 mRNA expression, enhanced caspase 3 protein concentrations and elevated caspase 3 activity indicate the involvement of these pathways in LVD after chronic pressure overload. These results suggest that binding of Fas to its receptor may lead to subsequent activation of caspase 3 [27]. No significant changes in the mRNA expression of other apoptotic genes were observed. Surprisingly we were not able to detect an involvement of bax or bcl-2 on mRNA-level. It has been previously shown by Condorelli et al. [3] that both bcl-2 and bax are upregulated on the protein level in rats with LVD due to aortic banding. In that study no mRNA were shown. It is conceivable that the induction of bcl-2 and bax may just be detectable at protein level. We were able to demonstrate, however, that the caspase 3 pathway is the dominant apoptotic mechanism in this chronic state of prolonged pressure overload.

This is the first study to provide evidence that both caspase 3 mRNA expression, caspase 3 protein levels and activity are upregulated in rats with LVD. The activation of caspase 3 is a key step for cells undergoing apoptosis. Since the upregulation of caspase 3 mRNA as well as the increased activity of caspase 3 occurs at a state where these rats had developed left ventricular dysfunction, caspase 3 might be involved in the deterioration of cardiac function.

The role of caspase 3 in the setting of heart failure remains complex. Recently, increased infarct size and depressed cardiac function after myocardial infarction was reported in a mouse model overexpressing caspase 3 [28]. Despite inducing an ultrastructural damage, caspase 3 did not trigger a full apoptotic response in the cardiomyocytes. These direct effects of caspase activation on cardiac function could be explained by results of Communal et al. [15], who demonstrated that caspase 3 activation directly targets components of the myofilaments. The cleavage of the proteins by caspase 3 had direct effects on myofilament activation and contractile function. These in vitro findings might explain our in vivo results that caspase 3 is upregulated and activated only in LVD but not in LVH. Further studies will be needed to elucidate this aspect.

The presence of induced caspase 3 gene expression and increased activity of caspase 3 in the heart after 30 days of chronic pressure overload suggests that the ongoing and sustained activation of caspase 3 as a known signal transducer of apoptosis may contribute to progressive LVD and thus it can be speculated that apoptosis might be involved in the progression of LVD. These results might be relevant for other disease states, like severe and chronic hypertension, which eventually progress into LVD. It will be interesting to investigate whether inhibition of caspases and Fas activation could prevent apoptosis and therefore transition from left ventricular hypertrophy to left ventricular dilatation and thus slow down disease progression.


   Acknowledgements
 
The authors thank Astrid Schiche, Jeannette Mothes, Jutta Meisel, Jeannine Rettschlag and Rita Günzel for excellent technical and secretarial assistance.


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

  1. Li Z., Bing O.H.L., Long X., Robinson K.G., Lakatta E.G. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol (1997) 272:H2313–H2319.[Web of Science][Medline]
  2. Narula J., Haider N., Virmani R., DiSalvo T., Kolodgie F.D., Hajjar R.J., et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med (1996) 335:1182–1189.[Abstract/Free Full Text]
  3. Condorelli G., Morisco C., Stassi G., Notte A., Farina F., Sgaramella G., et al. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation (1999) 99:3071–3078.[Abstract/Free Full Text]
  4. Nitahara J.A., Cheng W., Liu Y., Li B., Leri A., Li P., et al. Intracellular Calcium, DNase activity and myocyte apoptosis in aging fischer 344 rats. J Mol Cell Cardiol (1998) 30:519–535.[CrossRef][Web of Science][Medline]
  5. Teiger E., Dam T.-V., Richard L., Wisnewsky C., Tea B.-S., Gaboury L., et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest (1996) 97:2891–2897.[Web of Science][Medline]
  6. Badorff C., Ruetten H., Mueller S., Stahmer M., Gehring D., Jung F., et al. Fas receptor signaling inhibits glycogen synthase kinase 3{beta} and induces cardiac hypertrophy following pressure overload. J Clin Invest (2002) 109:373–381.[CrossRef][Web of Science][Medline]
  7. Wollert K.C., Heineke J., Westermann J., Ludde M., Fiedler B., Zierhut W., et al. The cardiac Fas (APO-1/CD95) receptor/Fas ligand system: relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Circulation (2000) 101:1172–1178.[Abstract/Free Full Text]
  8. Hunter J.J., Chien K.R. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med (1999) 341:1276–1283.[Free Full Text]
  9. MacLellan W.R., Schneider M.D. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res (1997) 81:137–144.[Abstract/Free Full Text]
  10. Nagata S. Apoptosis by death factor. Cell (1997) 88:355–365.[CrossRef][Web of Science][Medline]
  11. Chinnaiyan A.M., Dixit V.M. Portrait of an executioner: the molecular mechanism of Fas/ APO-1-induced apoptosis. Immunology (1997) 9:69–76.
  12. Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E.S. Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc Natl Acad Sci USA (1996) 93:14 486, 14491.
  13. Reed J.C. Warner–Lambert/Parke–Davis Award Lecture. Am J Pathol (2000) 157:1415–1430.[Abstract/Free Full Text]
  14. Saraste A., Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res (2000) 45:528–537.[Abstract/Free Full Text]
  15. Communal C., Sumandea M., deTombe P., Narula J., Solaro R.J., Hajjar R.J. Functional consequences of caspase activation in cardiac myocytes. PNAS (2002) 99:6252–6256.[Abstract/Free Full Text]
  16. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem (1987) 162:156–159.[Web of Science][Medline]
  17. Szabo A., Lutz J., Schleimer K., Antus B., Hamar P., Philipp T., et al. Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat. Kidney Int (2000) 57:982–991.[CrossRef][Web of Science][Medline]
  18. Refaeli Y., vanParijs L., London C.A., Tschopp J., Abbas A.K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity (1998) 8:615–623.[CrossRef][Web of Science][Medline]
  19. Orlov S.N., Thorin-Trescases N., Kotelevtsev S.V., Tremblay J., Hamet P. Inversion of the intracellular Na+/K+ ratio blocks apoptosis in vascular smooth muscle at a site upstream of caspase-3. J Biol Chem (1999) 274:16 545, 16552.
  20. Katz A.M., Epstein F.H. Cardiomyopathy of overload: a major determinant of prognosis in congestive heart failure. N Engl J Med (1990) 322:100–110.[Web of Science][Medline]
  21. Capasso J.M., Palackal T., Olivetti G., Anversa P. Left ventricular failure induced by long-term hypertension in rat. Circ Res (1990) 66:1400–1412.[Abstract/Free Full Text]
  22. Olivetti G., Abbi R., Quaini F., Kajstura J., Cheng W., Nitahara J.A., et al. Apoptosis in the failing human heart. N Engl J Med (1997) 336:1131–1141.[Abstract/Free Full Text]
  23. Hamet P., Moreau P., Dam T.-V., Orlov S.N., Tea B.-S., DeBlois D., et al. The time window of apoptosis: a new component in the therapeutic strategy for cardiovascular remodeling. J Hypertens (1996) 14:S65–S70.[Web of Science]
  24. Kajstura J., Cheng W., Reiss K., Clark W.A., Sonnenblick E.H., Krajewski S., et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest (1996) 74:86–107.[Web of Science][Medline]
  25. Fortuno M.A., Ravassa S., Etayo J.C., Diez J. Over expression of bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats. Hypertension (1998) 32:280–286.[Abstract/Free Full Text]
  26. 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) 73:184–192.[Abstract]
  27. Nishigaki K., Minatoguchi S., Seishima M., Asano K., Noda T., Yasuda N., et al. Plasma fas ligand,an inducer of apoptosis, and plasma soluble fas,an inhibitor of apoptosis, in patients with chronic congestive heart failure. J Am Coll Cardiol (1997) 29:1214–1220.[Abstract]
  28. Condorelli G., Roncarati R., Ross J., Pisani A., Stassi G., Todaro M., et al. Heart targeted over expression of caspase 3 in mice increases infarct size and depresses cardiac function. PNAS (2001) 98:9977–9982.[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
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. Niizeki, Y. Takeishi, T. Kitahara, T. Arimoto, M. Ishino, O. Bilim, S. Suzuki, T. Sasaki, O. Nakajima, R. A. Walsh, et al.
Diacylglycerol kinase-{varepsilon} restores cardiac dysfunction under chronic pressure overload: a new specific regulator of G{alpha}q signaling cascade
Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H245 - H255.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
J. Fielitz, S. Philipp, L. R. Herda, E. Schuch, B. Pilz, C. Schubert, V. Gunzler, R. Willenbrock, and V. Regitz-Zagrosek
Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding
Eur J Heart Fail, April 1, 2007; 9(4): 336 - 342.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
T. Hang, Z. Huang, S. Jiang, J. Gong, C. Wang, D. Xie, and H. Ren
Apoptosis in pressure overload-induced cardiac hypertrophy is mediated, in part, by adenine nucleotide translocator-1.
Ann. Clin. Lab. Sci., December 1, 2006; 36(1): 88 - 95.
[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 Philipp, S.
Right arrow Articles by Willenbrock, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Philipp, S.
Right arrow Articles by Willenbrock, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?