This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirshenbaum, L. A. Articles by de Moissac, D. Search for Related Content PubMed PubMed Citation Articles by Kirshenbaum, L. A. Articles by de Moissac, D.

(Circulation. 1997;96:1580-1585.)
© 1997 American Heart Association, Inc.

Articles

The bcl-2 Gene Product Prevents Programmed Cell Death of Ventricular Myocytes

Lorrie A. Kirshenbaum, PhD; ; Danielle de Moissac, MSc

From the Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.

Correspondence to Dr Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, Room 3042, 351 Taché Ave, Winnipeg, Manitoba, Canada R2H 2A6. E-mail Lorrie{at}SBRC.umanitoba.ca

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background To formally test whether the antiapoptotic protein bcl-2 would prevent programmed cell death in cardiac muscle cells provoked by p53, a known trigger of apoptosis in a variety of different cell types, we used replication defective adenovirus encoding either the bcl-2 and p53 genes to deliver bcl-2 and p53 to ventricular myocytes with high efficiency and uniformity.

Methods and Results Vital staining of ventricular myocytes revealed a significant (7-fold, P<.05) increase in myocyte cell death in the presence of p53 in contrast to uninfected cells or those infected with a control virus. In addition, in the presence of p53, nucleosomal DNA fragmentation observed by Hoescht 33258 staining and terminal transferase deoxynucleotide end labeling indicated a significant increase in apoptotic cardiac nuclei compared with control cells, confirming the hypothesis that p53 alone is sufficient to trigger apoptosis of ventricular myocytes. Moreover, a significant increase in transcription of the bax promoter was seen in the presence but not in the absence of p53 compared with control cells. Expression of the antiapoptotic gene bcl-2 in ventricular myocytes was sufficient to prevent ventricular myocyte death and apoptosis provoked by p53. Importantly, the antiapoptotic effects of bcl-2 were independent of altered p53 expression or localization of p53 to cardiac nuclei. However, p53 dependent transcription of bax was repressed 4-fold (P<.05) by bcl-2, suggesting a tentative link between p53-mediated apoptosis and the protective properties conferred by bcl-2 in ventricular myocytes.

Conclusions To our knowledge, the data provide the first indication for the operation of bcl-2 in ventricular myocytes as an antiapoptotic factor.

Key Words: apoptosis • adenovirus • cells • genes • molecular biology

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The occurrence of apoptosis in cardiac tissues has been recently described during hypoxia and ischemia-reperfusion and in the border zone after infarction.^{1 2 3 4 5} However, the molecular events that regulate programmed cell death in the myocardium remain unknown. Apoptosis is characterized by condensation of both nucleus and cytoplasm without the loss of membrane integrity.

Although the molecular pathways that govern apoptosis are poorly defined, there is increasing awareness that the p53 tumor suppressor protein may be involved in this process.^{6 7 8 9} That p53 may operate as a regulator of apoptosis is largely substantiated by studies in p53 knockout mice (-/-) and in cells derived from human tumors that had either lost or inactivated forms of p53.^{10 11 12} These cells exhibit unlimited growth potential with increased resistance to apoptosis.^{10 12} Replacement of wild-type p53 into p53-defective cells restored growth control and the ability for apoptosis.^{13 14}

The molecular mechanisms underlying p53-induced apoptosis in mammalian cells are obscure but may involve the transactivation by p53 of certain cellular genes that are involved in the apoptotic pathway. In this regard, transcription of the death-promoting gene bax has been shown to be upregulated by p53 and forms a potential link between p53 and programmed cell death.^{15 16 17} Precedence for the expression of p53 and Bax have been documented in cardiac tissue under different pathological conditions,^{5 18} but the spatial and temporal relationships of these proteins with respect to cardiac cell death remain enigmatic. Although bcl-2 and related family member Bclx_L share extensive amino acid homology to Bax and have been shown to prevent apoptosis provoked by a variety of signals, including those initiated by p53,^{19 20 21} their function in cardiac muscle has not been determined. Moreover, it is currently unknown whether the cytoprotective properties conferred by these proteins will be functionally equivalent in ventricular myocytes in response to apoptotic signals.

Thus, a better understanding of the mechanisms related to ventricular muscle cell death under normal and disease conditions would be of significant scientific value given the lack of de novo myocyte proliferation that occurs after injury. Therefore, to formally test for the operation of bcl-2 in ventricular myocytes as a potential antiapoptotic factor, we studied the impact of bcl-2 expression in postnatal ventricular myocytes on cardiac cell survival and cell death in the presence of p53, a known trigger of apoptosis implicated in cardiac cell death.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Cell Culture and Transfection
Neonatal ventricular myocytes were isolated from 2-day-old Sprague-Dawley rat hearts, subjected to Percoll gradient centrifugation, and submitted to primary culture as previously described^{22 23} After overnight incubation in Dulbecco's modified Eagle's medium/Ham's nutrient mixture F-12 (DF; 1:1), 17 mmol/L HEPES, 3 mmol/L NaHCO₃, 2 mmol/L l-glutamine, 50 µg/mL gentamicin, and 10% FBS, cells were transferred to serum-free medium.²² Myocyte cultures were infected with 20 plaque-forming units per cell of recombinant adenovirus that encode either p53 or bcl-2 gene products for 4 hr. This titer of virus achieves gene delivery to 95% of neonatal ventricular cells under these conditions.²² Myocytes were transfected immediately after removal of viral stocks for 1 hour with Dulbecco's modified Eagle's medium containing DEAE-dextran, 5.0 µg luciferase reporter gene, 2.5 µg CMVß-gal, 2.5% calf serum, and 10% dimethylsulfoxide.^{22 23} Myocytes were maintained in 10% FBS-DF and harvested 48 hours after transfection. To control for potential differences in transfection efficiency among different myocyte cultures, luciferase activity was normalized to ß-galactosidase activity and expressed as relative light units. The human Bax promoter consisted of nucleotides -318 to -688, which contains consensus p53 binding sites 5'-GAGACAAGCCTGGGCGTGGGGCT-3',¹⁷ was subcloned into BglII/SacI sites of the luciferase reporter plasmid PXP2 and designated BaxlucWT. A mutant version of this promoter construct, which has been shown previously to abrogate binding to p53,¹⁷ was constructed by subcloning nucleotides -415 to -508 of the bax promoter containing a four-nucleotide substitution within the p53 consensus binding region (underlined) 5'-GAGATAATGTGGGCGTAGGGCT-3'¹⁷ into the BglII/SalI sites of PXP2 and designated BaxlucMT. Data were obtained from at least five independent myocyte cultures with replicates of three for each condition. Results were compared by ANOVA and Student's unpaired two-tailed t test, using a significance level of P<.05.

Recombinant Adenoviruses
Adenoviruses were propagated, harvested, titered, and purified from human 293 cells as previously reported.^{22 24} AdCMVp53 denotes the 1.40-kb cDNA fragment of the human p53, driven by the human cytomegalovirus (CMV) immediate-early enhancer rescued into adenovirus background as previously described.²⁵ AdCMVbcl-2 denotes the full-length human bcl-2 c-DNA driven by the human CMV enhancer-promoter as previously described.²⁶ To control for the effects of viral infection alone, we used the adenovirus virus designated AdCMV, which contains the human CMV enhancer-promoter (kindly provided by J. Nevins).²⁷

Western Blot Analysis
For immunodetection of p53 and BAX in cardiac myocytes after adenovirus-mediated gene transfer, cardiac myocytes were harvested 48 hours after infection in 1.0% Nonidet P-40, 0.5% sodium dodecyl sulfate, 150 mmol/L NaCl, and 50 mmol/L Tris · HCl, pH 7.4. Cell lysates (25 µg) were resolved on a 12% sodium dodecyl sulfate-polyacrylamide gel at 200 V for 45 min and electrophoretically transferred to nitrocellulose membrane. For detection of p53, the nitrocellulose filter was incubated for 1 hour at room temperature with mouse antibody directed toward human p53 (clone 1801) (1 µg/mL; Oncogene Science) in 150 mmol/L NaCl, 50 mmol/L Tris · HCl, pH 7.4, 0.3% Tween-20, and 1.0% bovine serum albumin (TBS-Tween). For detection of BAX protein, the nylon filter was incubated overnight with a mouse monoclonal antibody directed toward human BAX protein in TBS-Tween (generously provided by J. Reed). The filter was washed three times in TBS-Tween and incubated with 0.5 µg/mL horseradish peroxidase-conjugated sheep antibody against mouse IgG (Amersham). Proteins were detected by chemiluminescence reaction using ECL reagents (Amersham).

Immunocytochemistry
After adenovirus-mediated gene transfer, live and dead cells were distinguished using the vital stains 2 µmol/L calcein acetoxymethyl ester and 2 µmol/L ethidium homodimer-1, respectively (Molecular Probes).²² To determine the relative abundance and appropriate targeting of p53 protein to cardiac nuclei after adenovirus infection by immunofluorescence microscopy, myocytes were incubated with 0.5 µg/mL murine antibody directed against human p53 (Oncogene Science) followed by 10 µg/mL rhodamine-conjugated sheep F(ab)'₂ anti-mouse IgG (Boehringer-Mannheim). Affinity-purified mouse IgG was used as an antibody control for immunocytochemistry experiments.

Assays of Apoptosis
To visualize nuclear morphology and nucleosomal DNA fragmentation of cardiac nuclei in the presence and absence of p53, myocytes were identified by indirect immunocytochemistry using MF20 hybridoma supernatant (1:5 dilution) against sarcomeric myosin heavy chain²⁸ and 10 µg/mL rhodamine-conjugated sheep F(ab)'₂ anti-mouse IgG (Boehringer-Mannheim) and counterstained with Hoechst dye 33258 for nuclear DNA. To visualize apoptotic nuclei in cardiac myocytes in situ, ventricular myocytes were identified for sarcomeric myosin heavy chain as described above and subjected to terminal transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay.²⁹ Myocytes were incubated for 1 hour at 37°C in 140 mmol/L sodium cacodylate, 1 mmol/L cobalt chloride, 30 mmol/L Tris · HCl, pH 7.2, 50 U terminal deoxynucleotide transferase, and 1 nmol fluorescein-conjugated dUTP (Boehringer-Mannheim). Myocytes that stained positive for both myosin heavy chain and incorporated biotin-dUTP in their nuclei were quantified as apoptotic.

	Results

Top Abstract Introduction Methods Results Discussion References

 
To determine whether the tumor suppressor protein p53 might trigger programmed cell death of cardiac myocytes and to establish whether the antiapoptotic gene bcl-2 could avert apoptosis, cardiac myocytes were infected with adenoviruses encoding either p53 or bcl-2 and stained with calcein acetoxymethyl ester and ethidium homodimer-1 to identify the live and dead cells, respectively (Fig 1). After 24 hours, myocytes infected with bcl-2 alone were indistinguishable from uninfected control cells with respect to viability, indicating that neither adenovirus infection nor the presence of Bcl-2 was cytotoxic to myocytes, a finding consistent with earlier observations using the same titer of virus.²² In contrast, in the absence of Bcl-2, p53 provoked a 7-fold increase in myocyte cell death compared with uninfected control cells or those with p53 plus Bcl-2 (P<.05). No difference in cell death was noted between uninfected control cells or those infected with Bcl-2 (P=.55). To confirm that p53 in the absence of Bcl-2 was cytotoxic to myocytes and triggered programmed cell death, we used indirect immunofluorescence microscopy for sarcomeric myosin heavy chain and Hoechst 33258 dye for nuclear DNA.²² The cells infected with p53 plus Bcl-2 did not differ from uninfected control cells (Fig 2A to 2C and 2G to 2I); however, cardiac muscle cells infected with p53 alone displayed evidence of cell rounding and nucleosomal fragmentation (Fig 2D to 2F). In addition, to confirm that p53 triggered apoptosis in ventricular myocytes, we assayed cardiac myocytes for the incorporation for biotinylated-dUTP using the TUNEL assay.²⁹ Again, cells infected with p53 plus Bcl-2 did not differ from uninfected control cells or those infected with Bcl-2 alone (P<.05) (Fig 3), which verified that neither virus infection nor the presence of Bcl-2 was cytotoxic to myocytes. In contrast, a 6-fold (P<.05) increase in biotinylated dUTP-labeled cells was observed with p53 in the absence of Bcl-2 (Fig 3), substantiating our findings that p53 provokes apoptosis in cardiac myocytes. Moreover, nucleosomal DNA laddering was observed with p53 but not with p53 plus Bcl-2 or Bcl-2 alone (not shown), a finding consistent with the percentage of TdT-labeled myocytes. To establish whether the antiapoptotic effects conferred by Bcl-2 were due to altered p53 expression or localization of p53 to cardiac nuclei, we used indirect immunofluorescence microscopy and Western blot analysis with a murine antibody directed toward human p53. As indicated by the rhodamine fluorescence (Fig 4C, 4D, 4E, and 4F), p53 was uniformly expressed and appropriately targeted to the nuclei of cardiac myocytes in the presence or absence of Bcl-2. Similarly, Western blot analysis of protein extracts from myocytes confirmed that p53 was expressed to comparable levels in the absence or presence of Bcl-2 (Fig 5A). Ponceau-S staining (Fig 5B) revealed equivalent loading of cardiac cell lysate. These findings indicate that the antiapoptotic properties imposed by Bcl-2 are independent of impaired transcription or translation of p53 itself but rather may impinge on alternative genes that lie downstream from p53 in the apoptotic pathway. In this regard, it has recently been shown that the proapoptotic gene bax can be activated by p53. To test this possibility, we transfected ventricular myocytes using conventional techniques with the human bax gene promoter luciferase constructs, which contain cis-acting p53 response elements. In the presence of p53, a 4-fold activation of the bax promoter was seen compared with uninfected control cells or those with Bcl-2 alone (P=.003 versus control, P=.001 versus Bcl-2, respectively; Fig 6). In contrast, p53-stimulated transcription of the bax promoter was repressed by 3.5-fold in the presence of Bcl-2 (P<.001). To rule out the possibility that repression of bax promoter transcription in the presence of p53 by Bcl-2 was due to nonspecific effects of viral infection or promoter competition, we transfected ventricular myocytes with bax promoter constructs after infection with a control virus AdCMV. Here, Bcl-2 but not the control virus AdCMV (Fig 6) significantly affected Bax promoter transcription in the presence of p53 (P<.05). To confirm that transactivation of the bax promoter by p53 was contingent on p53 binding, we generated bax promoter luciferase constructs with mutations engineered into the p53 response elements, which have been previously shown to abrogate p53 binding.¹⁷ Here, neither the promoterless luciferase construct nor mutations of the bax promoter that interfere with p53 binding were influenced by the control AdCMV, p53, Bcl-2, or combinations of both, indicating that p53-mediated transactivation as well as repression of the bax promoter in the presence of Bcl-2 was dependent on consensus p53 binding sites. Importantly, Western blot analysis confirmed a 3.3-fold induction of the endogenous p21Bax protein in the presence of p53 compared with uninfected control cells (densitometric analysis, 23.1 versus 76.8), a finding consistent with our transfection data (Fig 7).

View larger version (9K): [in this window] [in a new window]   Figure 1. p53 provokes widespread cell death in ventricular muscle cells that is prevented by Bcl-2. At 24 hours after infection, cells were visualized using calcein acetoxymethyl ester and ethidium homodimer-1 to determine the number of live versus dead cells. For uninfected control cells (CTL), p53, and p53 plus Bcl-2, values are mean±SEM for replicate cultures calculated using 100 cells for each condition shown. Independent experiments were repeated at least five times.

View larger version (105K): [in this window] [in a new window]   Figure 2. Bcl-2 rescues p53-mediated nuclear fragmentation in ventricular muscle cells. A to C, Uninfected cells; D to F, p53; G to I, p53 + Bcl-2; A, D, and G, phase contrast microscopy; and B, E, and H, epifluorescence microscopy using Hoechst dye 33258 for nuclear morphology (blue) and epifluorescence microscopy using MF20 antibody and rhodamine for sarcomeric myosin (red). Bar indicates 80 µm.

View larger version (8K): [in this window] [in a new window]   Figure 3. p53-provoked cell death of ventricular muscle cells with features typical of apoptosis that is averted by Bcl-2. B, Double staining of ventricular myocytes for the presence of DNA fragmentation by terminal deoxynucleotide end-labeling of biotin-dUTP16 (TdT) and MF20 antibody for sarcomeric myosin and rhodamine. Values are mean±SEM for ventricular myocytes that were simultaneously stained for myosin and TdT positive. Replicate cultures were calculated using 100 cells for each condition shown.

View larger version (88K): [in this window] [in a new window]   Figure 4. Uniform expression and appropriate localization of p53 protein to nuclei of ventricular myocytes in the presence or absence of Bcl-2. At 24 hours after infection, cells were stained for the presence of p53 protein. A and B, Uninfected cells; C and D, p53; E and F, p53 + Bcl-2; G and H, Bcl-2; A, C, E, and G, phase contrast microscopy; and B, D, F, and H, epifluorescence microscopy using a primary murine anti-p53 antibody and secondary rhodamine-conjugated anti-murine antibody.

View larger version (34K): [in this window] [in a new window]   Figure 5. Expression of p53 protein in ventricular myocytes. A, Cell lysates from adenovirus-infected cardiac myocytes were analyzed by sodium dodecyl sulfate-gel electrophoresis. p53 protein was visualized by Western blot analysis using a murine anti-p53 antibody directed against human p53 protein followed by horseradish peroxidase-conjugated anti-mouse IgG. B, Ponceau-S– stained filter to demonstrate equivalent protein loading of cardiac cell lysate.

View larger version (17K): [in this window] [in a new window]   Figure 6. Bcl-2 prevents p53-dependent transcription of bax gene transcription. p53-dependent transcription of bax promoter in the absence but not presence of Bcl-2. Values are mean±SEM (P<.05). p53 is unable to transactivate either the promoterless PXP2 luciferase vector or the bax promoter with site-directed mutations engineered into the p53 binding sites (see text for details). Experiments were repeated at least five times with independent culture conditions with three replicates for each condition.

View larger version (28K): [in this window] [in a new window]   Figure 7. p53 increases the expression of the endogenous Bax protein. Cell lysates from adenovirus-infected cardiac myocytes were analyzed by sodium dodecyl sulfate-gel electrophoresis. Bax protein was visualized by Western blot analysis using a mouse monoclonal antibody directed toward the Bax protein followed by horseradish peroxidase-conjugated anti-mouse IgG. Densitometric analysis indicated a 3.3-fold induction of the endogenous Bax protein in the presence of p53 compared with control.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
To our knowledge, the present experiments provide the first indication of the operation of Bcl-2 in ventricular myocytes as a potential antiapoptotic factor. Moreover, the data substantiate and confirm the involvement of the tumor suppressor protein p53 as a trigger for the induction of apoptosis in cardiac myocytes. Evidence for the occurrence of apoptosis in the cardiac tissue has recently been described in the vasculature^{1 30} and myocardium³¹ after hypoxia,² ischemia-reperfusion,³ and the border zone after infarction.^{4 5} Although terminally differentiated adult ventricular myocytes have traditionally been viewed as irreversibly exited from the cell cycle, there are some recent reports documenting a limited capacity of the adult myocyte to reenter the cell and synthesize DNA under certain pathological conditions, coincident with the occurrence of apoptosis.^{5 32} Hence, loss of potentially viable myocytes after injury may have profound implications with respect to cardiac structure and function. In this regard, conduction defects and ventricular arrhythmias have been suggested to emanate from inappropriate apoptosis of the sinoatrial, atrioventricular, and His-bundle fibers, respectively.³¹ Moreover, apoptotic cell death has been detected in restenotic and, to a lesser extent, in primary atherosclerotic lesions of the vasculature.¹

Although of considerable scientific and clinical importance, little is known of the molecular mechanisms that regulate programmed cell death in cardiac muscle cells. Potential clues from studies in transformed cells and other model systems suggest the involvement of the tumor suppressor protein p53.^{13 14 33} Evidence for the operation of p53 in cardiac muscle is strongly supported by studies in transgenic animals in which atrial and ventricular muscle growth was augmented by SV40 large T antigen, which disrupts p53 function.^{34 35} Apoptosis was not documented in this study, principally because the large T antigen binds to and inactivates p53. However, alternative viral proteins, including adenovirus E1A, that induce p53 expression can trigger apoptosis in a variety of different cell types, including ventricular myocytes.^{22 36} Expression of p53 has been documented in cardiac tissue under pathological conditions, yet a cause-and-effect relationship with respect to cardiac cell death has not been established.^{5 18}

As a first step toward identifying potential regulators of apoptosis in ventricular myocytes, we studied the impact of the antiapoptotic gene bcl-2 on cardiac cell survival and cell death in the presence and absence of the tumor suppressor protein p53, a known trigger of apoptosis implicated in provocation of cardiac myocyte death. Under these conditions, our data substantiate a role for p53 in the induction of ventricular myocyte death with features typical of apoptosis. Importantly, myocyte death provoked by p53 could be abrogated by the antiapoptotic gene bcl-2. Interestingly, the protective properties conferred by bcl-2 in ventricular myocytes were independent of altered p53 expression or localization of p53 to cardiac nuclei, suggesting alternative mechanisms may be in operation. Because the apoptosis-promoting gene bax³⁷ is known to be positively regulated by p53^{38 39} and has been detected in the border zone of myocardial infarcts along with p53,⁵ we examined the effect of p53 on bax promoter transcription. Our data indicate that p53 was able to direct transcription of the bax promoter with a concurrent increase in the endogenous Bax protein. However, p53-mediated transactivation of the bax promoter was impaired in the presence of Bcl-2, suggesting a potential link between the protective effect conferred by Bcl-2 in cardiac myocytes on p53-mediated apoptosis. Although provisional because protein/protein interactions were not determined here, it has been proposed that Bcl-2 and related family members may promote cell survival by titrating those factors that promote apoptotic cell death, such as Bax and Bad.^{21 40 41 42} Nevertheless, the data to our knowledge provide the first indication of the operation of Bcl-2 in neonatal ventricular myocytes as an antiapoptotic factor and substantiate the role of the tumor suppressor protein p53 as a trigger for apoptosis in ventricular myocytes. Whether Bcl-2 will equivalently function as a regulator of apoptosis in adult cardiac muscle remains to be determined. Future studies are directed toward determining the impact of Bax and other death-promoting signals in myocardial disease states and whether Bcl-2 will avert apoptosis in this context.

	Acknowledgments

 
This work was supported by grants from Heart and Stroke Foundation of Canada. Dr Kirshenbaum is a Scholar of the Heart and Stroke Foundation of Canada. We are grateful to J. Roth, G. Chinnadurai (for viruses cited), J. Reed (for bax reagents), P.K. Singal, A. Greenberg, G.N. Pierce, L. Hyrshko, and H. Weisman (for critical comments on the manuscript).

Received December 19, 1996; revision received March 3, 1997; accepted March 7, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Isner JM, Kearney M, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995;91:2703-2711.[Abstract/Free Full Text]

2. Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res. 1994;75:426-433.[Abstract/Free Full Text]

3. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 1994;94:1621-1628.

4. Kajstura J, Mansukhani M, Cheng W, Reiss K, Krajewski S, Reed JC, Quaini F, Sonnenblick EH, Anversa P. Programmed cell death and expression of the proto-oncogene bcl-2 in myocytes during postnatal maturation of the heart. Exp Cell Res. 1995;219:110-121.[Medline] [Order article via Infotrieve]

5. Kajstura J, Cheng W, Reiss K, Clark WAR, Sonnenblick EH, Krajewski S, Reed JC, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86-107.[Medline] [Order article via Infotrieve]

6. Oren M. The involvement of oncogenes and tumor suppressor genes in the control of apoptosis. Cancer Metast Rev. 1992;11:141-148.[Medline] [Order article via Infotrieve]

7. Malcomson RD, Oren M, Wyllie AH, Harrison DJ. p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs. Br J Cancer. 1995;72:952-957.[Medline] [Order article via Infotrieve]

8. Eizenberg O, Faber Elman A, Gottlieb E, Oren M, Rotter V, Schwartz M. Direct involvement of p53 in programmed cell death of oligodendrocytes. EMBO J. 1995;14:1136-1144.[Medline] [Order article via Infotrieve]

9. Oren M. Relationship of p53 to the control of apoptotic cell death. Semin Cancer Biol. 1994;5:221-227.[Medline] [Order article via Infotrieve]

10. Sah VP, Attardi LD, Mulligan GJ, Williams BO, Bronson RT, Jacks T. A subset of p53-deficient embryos exhibit exencephaly. Nat Genet. 1995;10:175-180.[Medline] [Order article via Infotrieve]

11. Symonds H, Krall L, Remington L, Saenz Robles M, Lowe S, Jacks T, Van Dyke T. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell. 1994;78:703-711.[Medline] [Order article via Infotrieve]

12. Lowe SW, Jacks T, Housman DE, Ruley HE. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Sci U S A. 1994;91:2026-2030.[Abstract/Free Full Text]

13. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes [see comments]. Nature. 1993;362:847-849.[Medline] [Order article via Infotrieve]

14. Slichenmyer WJ, Nelson WG, Slebos RJ, Kastan MB. Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res. 1993;53:4164-4168.[Abstract/Free Full Text]

15. El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman K, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler K, Vogelstein B. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169-1174.[Abstract/Free Full Text]

16. Haffner R, Oren M. Biochemical properties and biological effects of p53. Curr Opin Genet Dev. 1995;5:84-90.[Medline] [Order article via Infotrieve]

17. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80:293-299.[Medline] [Order article via Infotrieve]

18. Kim KK, Soonpaa MH, Daud AI, Koh GY, Kim JS, Field LJ. Tumor suppressor gene expression during normal and pathologic myocardial growth. J Biol Chem. 1994;269:22607-22613.[Abstract/Free Full Text]

19. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9:1799-1805.[Medline] [Order article via Infotrieve]

20. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74:609-619.[Medline] [Order article via Infotrieve]

21. Chao DT, Linette GP, Boise LH, White LS, Thompson CB, Korsmeyer SJ. Bcl-XL and Bcl-2 repress a common pathway of cell death. J Exp Med. 1995;182:821-828.[Abstract/Free Full Text]

22. Kirshenbaum LA, Schneider MD. Adenovirus E1A represses cardiac gene transcription and reactivates DNA synthesis in ventricular myocytes via alternative pocket protein- and p300-binding domains. J Biol Chem. 1995;270:7791-7794.[Abstract/Free Full Text]

23. Parker TG, Chow KL, Schwartz RJ, Schneider MD. Positive and negative control of the skeletal alpha-actin promoter in cardiac muscle: a proximal serum response element is sufficient for induction by basic fibroblast growth factor (FGF) but not for inhibition by acidic FGF. J Biol Chem. 1992;267:3343-3350.[Abstract/Free Full Text]

24. Kirshenbaum LA, MacLellan WR, Mazur W, French BA, Schneider MD. Highly efficient gene transfer into adult ventricular myocytes by recombinant adenovirus. J Clin Invest. 1993;92:381-387.

25. Drazan KE, Shen XD, Csete ME, Zhang WW, Roth JA, Busuttil RW, Shaked A. In vivo adenoviral-mediated human p53 tumor suppressor gene transfer and expression in rat liver after resection. Surgery. 1994;116:197-203.[Medline] [Order article via Infotrieve]

26. Subramanian T, Tarodi B, Chinnadurai G. p53-independent apoptotic and necrotic cell deaths induced by adenovirus infection: suppression by E1B 19K and Bcl-2 proteins. Cell Growth Differ. 1995;6:131-137.[Abstract]

27. Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol. 1995;69:2491-2500.[Abstract]

28. Bader D, Masaki T, Fischman DA. Immunochemical analysis of myosin heavy chain during avain myogenesis in vivo. Cell Biol. 1982;95:763-770.

29. Gavrieli Y, Sherman Y, Ben Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992;119:493-501.[Abstract/Free Full Text]

30. Cho A, Courtman DW, Langille BL. Apoptosis (programmed cell death) in arteries of the neonatal lamb. Circ Res. 1995;76:168-175.[Abstract/Free Full Text]

31. James TN. Normal and abnormal consequences of apoptosis in the human heart: from postnatal morphogenesis to paroxysmal arrhythmias. Circulation. 1994;90:556-573.[Abstract/Free Full Text]

32. Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest. 1995;73:771-787.[Medline] [Order article via Infotrieve]

33. Keren Tal I, Suh BS, Dantes A, Lindner S, Oren M, Amsterdam A. Involvement of p53 expression in cAMP-mediated apoptosis in immortalized granulosa cells. Exp Cell Res. 1995;218:283-295.[Medline] [Order article via Infotrieve]

34. Daud AI, Lanson NA Jr, Claycomb WC, Field LJ. Identification of SV40 large T-antigen-associated proteins in cardiomyocytes from transgenic mice. Am J Physiol. 1993;264:H1693-H1700.[Abstract/Free Full Text]

35. Field LJ. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science. 1988;239:1029-1033.[Abstract/Free Full Text]

36. Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993;7:546-554.[Abstract/Free Full Text]

37. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995;80:285-291.[Medline] [Order article via Infotrieve]

38. Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC, Fields LE, Lucas PJ, Stewart V, Alt FW, Loh DY. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science. 1993;261:1584-1588.[Abstract/Free Full Text]

39. Yin XM, Oltvai ZN, Korsmeyer SJ. Heterodimerization with Bax is required for Bcl-2 to repress cell death. Curr Top Microbiol Immunol. 1995;194:331-338.[Medline] [Order article via Infotrieve]

40. Lotem J, Sachs L. Regulation of bcl-2, bcl-x_L, and bax in the control of apoptosis by hematopoietic cytokines and dexamethasone. Cell Growth Differ. 1995;6:647-653.[Abstract]

41. Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A. 1995;92:7834-7838.[Abstract/Free Full Text]

42. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1-6.[Free Full Text]

This article has been cited by other articles:

				L. Venteo, T. Bourlet, F. Renois, F. Douche-Aourik, J.-F. Mosnier, G. Lorain De la Grand Maison, M. Pluot, B. Pozzetto, and L. Andreoletti Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis Eur. Heart J., November 19, 2009; (2009) ehp489v1. [Abstract] [Full Text] [PDF]

				Y. C. Jin, Y. S. Lee, Y. M. Kim, H. G. Seo, J. H. Lee, H. J. Kim, H. S. Yun-Choi, and K. C. Chang (S)-1-({alpha}-Naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) Reduces Rat Myocardial Apoptosis against Ischemia and Reperfusion Injury by Activation of Phosphatidylinositol 3-Kinase/Akt Signaling and Anti-inflammatory Action in Vivo J. Pharmacol. Exp. Ther., August 1, 2009; 330(2): 440 - 448. [Abstract] [Full Text] [PDF]

				S. Wisel, M. Khan, M. L. Kuppusamy, I. K. Mohan, S. M. Chacko, B. K. Rivera, B. C. Sun, K. Hideg, and P. Kuppusamy Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 543 - 550. [Abstract] [Full Text] [PDF]

				G. H. Li, Y. Shi, Y. Chen, M. Sun, S. Sader, Y. Maekawa, S. Arab, F. Dawood, M. Chen, G. De Couto, et al. Gelsolin Regulates Cardiac Remodeling After Myocardial Infarction Through DNase I-Mediated Apoptosis Circ. Res., April 10, 2009; 104(7): 896 - 904. [Abstract] [Full Text] [PDF]

				V. Champattanachai, R. B. Marchase, and J. C. Chatham Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2 Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1509 - C1520. [Abstract] [Full Text] [PDF]

				R. M. Mentzer Jr, M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2008; 3(2008): 443 - 464. [Full Text]

				M. A. Nordlie, L. E. Wold, B. Z. Simkhovich, C. Sesti, and R. A. Kloner Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion-Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 17 - 30. [Abstract] [PDF]

				L. Zhang Prenatal Hypoxia and Cardiac Programming Reproductive Sciences, January 1, 2005; 12(1): 2 - 13. [Abstract] [PDF]

				K. M. Regula, M. J. Rzeszutek, D. Baetz, C. Seneviratne, and L. A. Kirshenbaum Therapeutic opportunities for cell cycle re-entry and cardiac regeneration Cardiovasc Res, December 1, 2004; 64(3): 395 - 401. [Abstract] [Full Text] [PDF]

				K. Imahashi, M. D. Schneider, C. Steenbergen, and E. Murphy Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury Circ. Res., October 1, 2004; 95(7): 734 - 741. [Abstract] [Full Text] [PDF]

				C. Sesti and R. A. Kloner Gene Therapy in Congestive Heart Failure Circulation, July 20, 2004; 110(3): 242 - 243. [Full Text] [PDF]

				T. Kawamura, K. Ono, T. Morimoto, M. Akao, E. Iwai-Kanai, H. Wada, N. Sowa, T. Kita, and K. Hasegawa Endothelin-1-Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac Myocytes Circ. Res., June 11, 2004; 94(11): 1492 - 1499. [Abstract] [Full Text] [PDF]

				T. Tokudome, T. Horio, M. Fukunaga, H. Okumura, J. Hino, K. Mori, F. Yoshihara, S.-I. Suga, Y. Kawano, M. Kohno, et al. Ventricular Nonmyocytes Inhibit Doxorubicin-Induced Myocyte Apoptosis: Involvement of Endogenous Endothelin-1 as a Paracrine Factor Endocrinology, May 1, 2004; 145(5): 2458 - 2466. [Abstract] [Full Text] [PDF]

				W. Bao, E. Hu, L. Tao, R. Boyce, R. Mirabile, D. T Thudium, X.-l. Ma, R. N Willette, and T.-l. Yue Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 548 - 558. [Abstract] [Full Text] [PDF]

				N. Weisleder, G. E. Taffet, and Y. Capetanaki Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy PNAS, January 20, 2004; 101(3): 769 - 774. [Abstract] [Full Text] [PDF]

				S. Bae, Y. Xiao, G. Li, C. A. Casiano, and L. Zhang Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H983 - H990. [Abstract] [Full Text] [PDF]

				D. M. Valks, T. J. Kemp, and A. Clerk Regulation of Bcl-xL Expression by H2O2 in Cardiac Myocytes J. Biol. Chem., July 3, 2003; 278(28): 25542 - 25547. [Abstract] [Full Text] [PDF]

				R. M. Mentzer Jr., M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2003; 2(2003): 413 - 438. [Full Text]

				Z.-Q. Zhao and J. Vinten-Johansen Myocardial apoptosis and ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 438 - 455. [Abstract] [Full Text] [PDF]

				H. Jankala, C. J. P. Eriksson, K. K. Eklund, M. Harkonen, and T. Maki COMBINED CALCIUM CARBIMIDE AND ETHANOL TREATMENT INDUCES HIGH BLOOD ACETALDEHYDE LEVELS, MYOCARDIAL APOPTOSIS AND ALTERED EXPRESSION OF APOPTOSIS-REGULATING GENES IN RAT Alcohol Alcohol., May 1, 2002; 37(3): 222 - 228. [Abstract] [Full Text] [PDF]

				C. GILL, R. MESTRIL, and A. SAMALI Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? FASEB J, February 1, 2002; 16(2): 135 - 146. [Abstract] [Full Text] [PDF]

				T. Suhara, H.-S. Kim, L. A. Kirshenbaum, and K. Walsh Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation Mol. Cell. Biol., January 15, 2002; 22(2): 680 - 691. [Abstract] [Full Text] [PDF]

				S. C. Stoica, D. K. Satchithananda, J. Dunning, and S. R. Large Two-decade analysis of cardiac storage for transplantation Eur. J. Cardiothorac. Surg., October 1, 2001; 20(4): 792 - 798. [Abstract] [Full Text] [PDF]

				F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]

				D. Ekhterae, O. Platoshyn, S. Krick, Y. Yu, S. S. McDaniel, and J. X.-J. Yuan Bcl-2 decreases voltage-gated K+ channel activity and enhances survival in vascular smooth muscle cells Am J Physiol Cell Physiol, July 1, 2001; 281(1): C157 - C165. [Abstract] [Full Text] [PDF]

				L. A. Kirshenbaum Death-Defying Pathways Linking Cell Cycle and Apoptosis Circ. Res., May 25, 2001; 88(10): 978 - 980. [Full Text] [PDF]

				Z. Chen, C. C. Chua, Y.-S. Ho, R. C. Hamdy, and B. H. L. Chua Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2313 - H2320. [Abstract] [Full Text] [PDF]

				R. M. Gurevich, K. M. Regula, and L. A. Kirshenbaum Serpin Protein CrmA Suppresses Hypoxia-Mediated Apoptosis of Ventricular Myocytes Circulation, April 17, 2001; 103(15): 1984 - 1991. [Abstract] [Full Text] [PDF]

				G. Taimor Cardiac gap junctions: good or bad? Cardiovasc Res, October 1, 2000; 48(1): 8 - 10. [Full Text] [PDF]

				S. Mustapha, A. Kirshner, D. De Moissac, and L. A. Kirshenbaum A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H939 - H945. [Abstract] [Full Text] [PDF]

				R. J. Hajjar, F. del Monte, T. Matsui, and A. Rosenzweig Prospects for Gene Therapy for Heart Failure Circ. Res., March 31, 2000; 86(6): 616 - 621. [Abstract] [Full Text] [PDF]

				C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]

				G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [Abstract] [Full Text] [PDF]

				M. Rezvani, J.D. Barrans, K.-S. Dai, and C.-C. Liew Apoptosis-related genes expressed in cardiovascular development and disease: an EST approach Cardiovasc Res, February 1, 2000; 45(3): 621 - 629. [Abstract] [Full Text] [PDF]

				H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao, M. Nakamura, N.-P. Wang, J. N. Wilcox, S. Shearer, R. S. Ronson, R. A. Guyton, and J. Vinten-Johansen Reperfusion induces myocardial apoptotic cell death Cardiovasc Res, February 1, 2000; 45(3): 651 - 660. [Abstract] [Full Text] [PDF]

				M. Nakamura, N.-P. Wang, Z.-Q. Zhao, J. N Wilcox, V. Thourani, R. A Guyton, and J. Vinten-Johansen Preconditioning decreases Bax expression, PMN accumulation and apoptosis in reperfused rat heart Cardiovasc Res, February 1, 2000; 45(3): 661 - 670. [Abstract] [Full Text] [PDF]

				A. Haunstetter and S. Izumo Future perspectives and potential implications of cardiac myocyte apoptosis Cardiovasc Res, February 1, 2000; 45(3): 795 - 801. [Abstract] [Full Text] [PDF]

				T. Matsui, L. Li, F. del Monte, Y. Fukui, T. F. Franke, R. J. Hajjar, and A. Rosenzweig Adenoviral Gene Transfer of Activated Phosphatidylinositol 3'-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro Circulation, December 7, 1999; 100(23): 2373 - 2379. [Abstract] [Full Text] [PDF]

				S. A. Cook, P. H. Sugden, and A. Clerk Regulation of Bcl-2 Family Proteins During Development and in Response to Oxidative Stress in Cardiac Myocytes : Association With Changes in Mitochondrial Membrane Potential Circ. Res., November 12, 1999; 85(10): 940 - 949. [Abstract] [Full Text] [PDF]

				S.A. Cook and P.A. Poole-Wilson Cardiac myocyte apoptosis Eur. Heart J., November 2, 1999; 20(22): 1619 - 1629. [PDF]

				D. de Moissac, H. Zheng, and L. A. Kirshenbaum Linkage of the BH4 Domain of Bcl-2 and the Nuclear Factor kappa B Signaling Pathway for Suppression of Apoptosis J. Biol. Chem., October 8, 1999; 274(41): 29505 - 29509. [Abstract] [Full Text] [PDF]

				S Westaby, O Franklin, and M Burch New developments in the treatment of cardiac failure Arch. Dis. Child., September 1, 1999; 81(3): 276 - 277. [Full Text]

				E. Iwai-Kanai, K. Hasegawa, M. Araki, T. Kakita, T. Morimoto, and S. Sasayama {alpha}- and {beta}-Adrenergic Pathways Differentially Regulate Cell Type–Specific Apoptosis in Rat Cardiac Myocytes Circulation, July 20, 1999; 100(3): 305 - 311. [Abstract] [Full Text] [PDF]

				R. von Harsdorf, P.-F. Li, and R. Dietz Signaling Pathways in Reactive Oxygen Species–Induced Cardiomyocyte Apoptosis Circulation, June 8, 1999; 99(22): 2934 - 2941. [Abstract] [Full Text] [PDF]

				K. Baghelai, L. J. Graham, A. S. Wechsler, and E. R. Jakoi DELAYED MYOCARDIAL PRECONDITIONING BY {{alpha}}1-ADRENOCEPTORS INVOLVES INHIBITION OF APOPTOSIS J. Thorac. Cardiovasc. Surg., May 1, 1999; 117(5): 980 - 986. [Abstract] [Full Text] [PDF]

				A. Stempien-Otero, A. Karsan, C. J. Cornejo, H. Xiang, T. Eunson, R. S. Morrison, M. Kay, R. Winn, and J. Harlan Mechanisms of Hypoxia-induced Endothelial Cell Death. ROLE OF p53 IN APOPTOSIS J. Biol. Chem., March 19, 1999; 274(12): 8039 - 8045. [Abstract] [Full Text] [PDF]

				P. K Singal, N. Khaper, V. Palace, and D. Kumar The role of oxidative stress in the genesis of heart disease Cardiovasc Res, December 1, 1998; 40(3): 426 - 432. [Abstract] [Full Text] [PDF]

				D. de Moissac, S. Mustapha, A. H. Greenberg, and L. A. Kirshenbaum Bcl-2 Activates the Transcription Factor NFkappa B through the Degradation of the Cytoplasmic Inhibitor Ikappa Balpha J. Biol. Chem., September 11, 1998; 273(37): 23946 - 23951. [Abstract] [Full Text] [PDF]

				M. A. Fortuno, S. Ravassa, J. C. Etayo, and J. Diez Overexpression of Bax Protein and Enhanced Apoptosis in the Left Ventricle of Spontaneously Hypertensive Rats : Effects of AT1 Blockade With Losartan Hypertension, August 1, 1998; 32(2): 280 - 286. [Abstract] [Full Text] [PDF]

				J. A. Dominov, J. J. Dunn, and J. B. Miller Bcl-2 Expression Identifies an Early Stage of Myogenesis and Promotes Clonal Expansion of Muscle Cells J. Cell Biol., July 27, 1998; 142(2): 537 - 544. [Abstract] [Full Text] [PDF]

				A. Haunstetter and S. Izumo Apoptosis : Basic Mechanisms and Implications for Cardiovascular Disease Circ. Res., June 15, 1998; 82(11): 1111 - 1129. [Full Text] [PDF]

				Q. N. Diep, M. El Mabrouk, P. Yue, and E. L. Schiffrin Effect of AT1 receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1635 - H1641. [Abstract] [Full Text] [PDF]

				T. Kakita, K. Hasegawa, E. Iwai-Kanai, S. Adachi, T. Morimoto, H. Wada, T. Kawamura, T. Yanazume, and S. Sasayama Calcineurin Pathway Is Required for Endothelin-1-Mediated Protection Against Oxidant Stress-Induced Apoptosis in Cardiac Myocytes Circ. Res., June 22, 2001; 88(12): 1239 - 1246. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirshenbaum, L. A. Articles by de Moissac, D. Search for Related Content PubMed PubMed Citation Articles by Kirshenbaum, L. A. Articles by de Moissac, D.