Skip Navigation


Cardiovascular Research Advance Access originally published online on November 20, 2007
Cardiovascular Research 2008 77(3):448-451; doi:10.1093/cvr/cvm074
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
77/3/448    most recent
cvm074v3
cvm074v2
cvm074v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
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 ISI Web of Science
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 Sanchis, D.
Right arrow Articles by Comella, J. X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sanchis, D.
Right arrow Articles by Comella, J. X.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

An alternative view of apoptosis in heart development and disease

Daniel Sanchis*, Marta Llovera, Manel Ballester and Joan X. Comella{dagger}

Cell Signaling and Apoptosis Group, Biomedical Research Institute of Lleida (IRBLLEIDA), Av. Rovira Roure, 80, 25198 Lleida Spain

* Corresponding author. Tel: +34 973702215; fax: +34 973702213. E-mail address: daniel.sanchis{at}cmb.udl.cat

Although the involvement of caspases in cardiomyocyte death is widely accepted [reviewed in1], increasing experimental evidence suggests that caspase activation is not relevant for post-mitotic cardiomyocyte cell death.2–7 Controversy also exists as to the mechanisms conferring cardioprotection by caspase inhibitors, which could be unrelated to apoptosis or target non-myocardial cells.8–11 In addition, the genes controlling the caspase-dependent death pathway are silenced during early post-natal development.7,12 Finally, the major role of death receptors and the Bcl-2-related proteins in the myocardium is probably to control differentiation, adaptation to stress and mitochondrial integrity. In light of these findings, we propose here an alternative explanation of the role of canonical apoptosis regulators in the control of cardiomyocyte life and death.


   1. Caspase-dependent signalling is important during heart morphogenesis and is later silenced in post-mitotic cardiomyocytes
Top
 1. Caspase-dependent signalling...
2. Mitochondrial damage...
 3. Death receptor-dependent...
 4. Death receptors play...
 5. Concluding remarks
 Funding
 References
 
Cell death implying apoptotic-like DNA damage occurs during embryonic heart development.13–15 Experiments using caspase inhibitors suggest that caspase-dependent cell death occurs in the cardiac regions submitted to important morphological changes, such as the ventriculoarterial connections, the atrioventricular cushions, and the conduction tissue.16–18 Therefore, caspase activation is likely assuring the proper formation of the cardiac cavities and the correct docking of the arteries to the ventricles during development. Later, the caspase-dependent death machinery is repressed during cardiomyocyte terminal differentiation,7,12 as it has been described in retinal neurons.19


   2. Mitochondrial damage implicated in post-mitotic cardiomyocyte death is not associated with caspase activation
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
3. Death receptor-dependent...
 4. Death receptors play...
 5. Concluding remarks
 Funding
 References
 
Many reports have demonstrated that mitochondrial damage precedes post-mitotic cardiomyocyte cell death and have suggested the involvement of caspases20 yet the engagement of these proteases downstream of mitochondrial damage is still debated [e.g. 4 vs. 21]. The Bcl-2 family controls mitochondrial events leading to caspase activation by regulating outer mitochondrial membrane permeabilization. However, mitochondrial damage also hinders aerobic metabolism and alters cellular Ca2+ homeostasis. Thus, Bcl-2 and Bcl-XL-dependent cardioprotection could be achieved by maintaining mitochondrial physiology through preservation of mitochondrial membrane integrity.22–25 Further, supporting a role of mitochondrial damage unrelated to caspases yet involving Bcl-2-related proteins, Bnip3 induces caspase-independent mitochondrial permeabilization during cardiac ischaemia.5 In this setting, myocyte DNA degradation is independent of caspases.5,7 In addition, high expression of Bcl-2 is suggested to limit autophagy in the heart.26 Because of its relevance in cardiomyocyte homeostasis,3,27–29 autophagy is a process controlled by the Bcl-2 family that could affect cardiomyocyte viability.

Another event involved in mitochondrial damage is the destabilization of the inner mitochondrial membrane integrity (mitochondrial permeability transition, MPT). MPT dissipates the electrochemical gradient, affecting aerobic energy production, and triggering the release of mitochondrial proteins to the cytosol.30 In cardiomyocytes, MPT is implied in cell death in a caspase-independent and Bcl-2-independent manner during ischaemia and reperfusion.31 In addition, caspase-independent calpain activation ensuing from mitochondrial damage could also impair Na+/K+ exchanger function, and hence Ca2+ homeostasis, exacerbating cardiac cell death during reperfusion.4,32 Moreover, an increase in the cytosolic Ca2+ pool could aggravate mitochondrial damage by increasing the cyclophilin-D-dependent MPT.31 Finally, the antiapoptotic protein ARC (Apoptotic Repressor with CARD domain)33,34 that has been shown to safeguard the heart34 and to block caspase activation in cell lines35,36 can also protect from caspase-independent death,37,38 suggesting that ARC-dependent protection could be caspase-independent in post-mitotic cardiomyocytes.

The above evidences suggest that mitochondrial damage is an important event leading to cardiomyocyte death without downstream activation of caspases. Our results show that the disruption between cytochrome c release and caspase activity is due to the silencing of key pro-apoptotic genes including Apaf-1 and executioner caspases during cardiac development [6,7, see Figure 1]. This could be an evolutionary selection to prevent death of long-lived cardiomyocytes after release of cytochrome c in order to sustain viability in case of mitochondrial rupture.


Figure 1
View larger version (75K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Literature-based hypothesis on the role of the caspase-dependent signalling cascade and the Bcl-2 protein family in the biology of the cardiomyocyte. In the cardiac embryonic cell (upper left panel), all the components of the caspase-dependent signalling pathway as well as the Bcl-2 family of proteins are expressed. The death receptor pathway is involved in myocardial differentiation by unknown mechanisms. Expression of Bcl-2 could account for the low autophagic activity. In the forming heart, some cells die by caspase-dependent mechanisms, although the relative contribution of the different pathways remains to be resolved (lower left panel). At the end of the terminal differentiation process (upper right panel), cardiomyocytes have lost the expression of the caspase-dependent signalling cascade. Reduction in the expression of Bcl-2 allows an increase in basal autophagy, which helps in maintaining the homeostasis of these long-lived cells. Some components of the death receptor pathway could be involved in the hypertrophic response of adult cardiomyocytes, in addition to the well-known role of calcineurin A (CnA). Maladaptive hypertrophy, exacerbated autophagy and other harmful events lead to caspase-independent mitochondrial permeability transition (MPT), cytochrome c release and calcium signalling alterations, leading to cell dysfunction and death. In this diagram, other relevant pathways involved in cardioprotection, as well as the contribution of the sarcoplasmic reticulum (SPR), have been omitted for clarity. a-Bax, activated Bax; C3/7, caspases 3 and 7; C8, caspase-8; C9, caspase-9; CypD, cyclophilin-D; Cyt C, cytochrome c; DISC, death-inducing signalling complex; TRADD, TNF receptor-associated death domain.

 

   3. Death receptor-dependent apoptosis is involved in non-myocyte cell death in experimental models of heart disease
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
 3. Death receptor-dependent...
4. Death receptors play...
 5. Concluding remarks
 Funding
 References
 
Fas-dependent signalling has been implicated in cardiomyocyte death during graft rejection and ischaemia/reoxygenation, as suggested by experiments comparing cardiomyocyte death in wild type mice and mice carrying loss-of-function mutations of either Fas or Fas ligand (FasL) genes (lpr and gld mice, respectively).39–41 However, it has been demonstrated that cardiac graft salvage in lpr and gld mice is due to a general impairment of the host immune response, which normally would attack the graft, and not to a specific role of cardiac Fas signalling.42 During ischaemia/reoxygenation-induced cardiomyocyte death, Fas and FasL have been shown recently to promote granulation tissue death but not cardiomyocyte loss.43,44 These results agree with the finding that the main role of caspase inhibitors given during experimental myocardial infarction is to protect non-myocardial cells.11 Tumor necrosis factor-{alpha} (TNF-{alpha}) was reported to induce DNA damage in cultured adult cardiomyocytes, although the involvement of caspases was not checked.45 However, recent reports using biochemical and genetic approaches have discarded a direct role of this cytokine in cardiomyocyte death.46–51 TNF-{alpha} genetic deficiency reduced cardiac inflammation and fibrosis, suggesting a role of TNF-{alpha} in granulation tissue signalling.51 Interestingly, TNF-{alpha} also induces caspase activation in vascular endothelial cells,52 which dye by apoptosis during congestive heart failure.53 Therefore, the extrinsic pathway likely induces granulation tissue and endothelial cell death but not cardiomyocyte death during heart disease.


   4. Death receptors play a relevant role in cardiomyocyte differentiation and growth
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
 3. Death receptor-dependent...
 4. Death receptors play...
5. Concluding remarks
 Funding
 References
 
Against expectation, null mutation of some components of the death receptor pathway, such as Fas-associated death domain (FADD), caspase-8 and cFLIP, a caspase-8-like protein that lacks the protease motif, induce ventricular cell hypoplasia and non compaction of the ventricular wall in the embryo.54–56 Interestingly, the role of these proteins in heart development seems to be independent of cell death because deficiency in the pro-apoptotic factors FADD and caspase-8, as well as lack of anti-apoptotic cFLIP, result in the same cardiac phenotype. On the contrary, experimental overexpression of Fas or FasL induces hypertrophy in cardiomyocytes.57–59 Cardiac hypertrophy ensues also from TNF-{alpha} stimulation in vitro46,47 and in vivo.48–49 In addition, mice lacking TNF receptors 1 and 2 have larger infarct areas than wild-type animals,50 and TNF-{alpha} genetic deficiency decreases the hypertrophic growth of the myocardium after aortic banding.51 These data suggest that cardiac death receptor activation triggers hypertrophy. Therefore, genetic and biochemical evidences suggest that the extrinsic pathway regulates cardiomyocyte differentiation and cardiac response to stress through cell death-independent mechanisms that remain to be explored.


   5. Concluding remarks
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
 3. Death receptor-dependent...
 4. Death receptors play...
 5. Concluding remarks
Funding
 References
 
In our opinion, there is solid evidence suggesting that although caspase-dependent cell death is involved in heart morphogenesis, post-mitotic cardiomyocyte death is a caspase-independent event. This shift could come after the repression of pro-apoptotic genes in cardiomyocytes during differentiation (see Figure 1). Caspase activation would affect indirectly post-mitotic myocyte cell survival and heart performance because it induces death of endothelial cells and granulation tissue. On the contrary, post-mitotic cardiomyocyte death would ensue from mitochondrial damage, which hampers aerobic respiration and alters calcium homeostasis in the absence of caspases. In addition, death receptors and the Bcl-2 family regulate events that are essential for cardiac function, such as cell differentiation and mitochondrial integrity, and modulate the response to stress by inducing hypertrophy and controlling autophagy. The full comprehension of these events will have great therapeutic potential.

Conflict of interest: none declared.


   Funding
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
 3. Death receptor-dependent...
 4. Death receptors play...
 5. Concluding remarks
 Funding
References
 
Ministry of Education and Science of Spain (SAF2005-02197 to D.S.).

Comissionat per a Universitats i Recerca-Government of Catalonia (‘Suport als Grups de Recerca de Catalunya’ conjoint grant to J.X.C., D.S. and M.L.).

Ministry of Education and Science of Spain (‘Ramón y Cajal’ contract to D.S. and M.L.).


   Notes
 
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

{dagger} Present address. Universitat Autònoma de Barcelona (UAB), Edifici M Campus Bellaterra, 08193 Bellaterra, Spain. Back


   References
Top
 1. Caspase-dependent signalling...
 2. Mitochondrial damage...
 3. Death receptor-dependent...
 4. Death receptors play...
 5. Concluding remarks
 Funding
 References
 

  1. Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. J Clin Invest (2005) 115:565–571.[CrossRef][Web of Science][Medline]
  2. Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y, Minatoguchi S, et al. ‘Apoptotic’ myocytes in infarct area in rabbit hearts may be oncotic myocytes with DNA fragmentation: analysis by immunogold electron microscopy combined with In situ nick end-labeling. Circulation (1998) 98:1422–1430.[Abstract/Free Full Text]
  3. Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM. Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res (2001) 51:304–312.[Abstract/Free Full Text]
  4. Chen M, Won DJ, Krajewski S, Gottlieb RA. Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem (2002) 277:29181–29186.[Abstract/Free Full Text]
  5. Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc Natl Acad Sci USA (2002) 99:12825–12830.[Abstract/Free Full Text]
  6. Sanchis D, Mayorga M, Ballester M, Comella JX. Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes. Cell Death Differ (2003) 10:977–986.[CrossRef][Web of Science][Medline]
  7. Bahi N, Zhang J, Llovera M, Ballester M, Comella JX, Sanchis D. Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J Biol Chem (2006) 281:22943–22952.[Abstract/Free Full Text]
  8. Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation (1998) 97:276–281.[Abstract/Free Full Text]
  9. Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura S, et al. Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res (2000) 45:642–650.[Abstract/Free Full Text]
  10. Ruetten H, Badorff C, Ihling C, Zeiher AM, Dimmeler S. Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects. J Am Coll Cardiol (2001) 38:2063–2070.[Abstract/Free Full Text]
  11. Hayakawa K, Takemura G, Kanoh M, Li Y, Koda M, Kawase Y, et al. Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage. Circulation (2003) 108:104–109.[Abstract/Free Full Text]
  12. Madden SD, Donovan M, Cotter TG. Key apoptosis regulating proteins are down-regulated during postnatal tissue development. Int J Dev Biol (2007) 51:415–423.[CrossRef][Web of Science][Medline]
  13. Takeda K, Yu ZX, Nishikawa T, Tanaka M, Hosoda S, Ferrans VJ, et al. Apoptosis and DNA fragmentation in the bulbus cordis of the developing rat heart. J Mol Cell Cardiol (1996) 28:209–215.[CrossRef][Web of Science][Medline]
  14. Watanabe M, Choudhry A, Berlan M, Singal A, Siwik E, Mohr S, et al. Developmental remodeling and shortening of the cardiac outflow tract involves myocyte programmed cell death. Development (1998) 125:3809–3820.[Abstract]
  15. Ya J, van den Hoff MJ, de Boer PA, Tesink-Taekema S, Franco D, Moorman AF, et al. Normal development of the outflow tract in the rat. Circ Res (1998) 82:464–472.[Abstract/Free Full Text]
  16. Schaefer KS, Doughman YQ, Fisher SA, Watanabe M. Dynamic patterns of apoptosis in the developing chicken heart. Dev Dyn (2004) 229:489–499.[CrossRef][Web of Science][Medline]
  17. Cheng G, Wessels A, Gourdie RG, Thompson RP. Spatiotemporal and tissue specific distribution of apoptosis in the developing chick heart. Dev Dyn (2002) 223:119–133.[CrossRef][Web of Science][Medline]
  18. Watanabe M, Jafri A, Fisher SA. Apoptosis is required for the proper formation of the ventriculo-arterial connections. Dev Biol (2001) 240:274–288.[CrossRef][Web of Science][Medline]
  19. Donovan M, Doonan F, Cotter TG. Decreased expression of pro-apoptotic Bcl-2 family members during retinal development and differential sensitivity to cell death. Dev Biol (2006) 291:154–161.[CrossRef][Web of Science][Medline]
  20. Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res (2004) 95:957–970.[Abstract/Free Full Text]
  21. Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res (2000) 87:118–125.[Abstract/Free Full Text]
  22. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol (2001) 280:H2313–H2320.[Abstract/Free Full Text]
  23. Huang J, Ito Y, Morikawa M, Uchida H, Kobune M, Sasaki K, et al. Bcl-xL gene transfer protects the heart against ischemia/reperfusion injury. Biochem Biophys Res Commun (2003) 311:64–70.[CrossRef][Web of Science][Medline]
  24. Imahashi K, Schneider MD, Steenbergen C, Murphy E. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res (2004) 95:734–741.[Abstract/Free Full Text]
  25. Tanaka M, Nakae S, Terry RD, Mokhtari GK, Gunawan F, Balsam LB, et al. Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease. Blood (2004) 104:3789–3796.[Abstract/Free Full Text]
  26. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell (2005) 122:927–939.[CrossRef][Web of Science][Medline]
  27. Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ (2007) 14:146–157.[CrossRef][Web of Science][Medline]
  28. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med (2007) 13:619–624.[CrossRef][Web of Science][Medline]
  29. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest (2007) 117:1782–1793.[CrossRef][Web of Science][Medline]
  30. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev (2007) 87:99–163.[Abstract/Free Full Text]
  31. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature (2005) 434:658–662.[CrossRef][Medline]
  32. Inserte J, Garcia-Dorado D, Hernando V, Soler-Soler J. Calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion contributes to cell death after myocardial ischemia. Circ Res (2005) 97:465–473.[Abstract/Free Full Text]
  33. Koseki T, Inohara N, Chen S, Nunez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci USA (1998) 95:5156–5160.[Abstract/Free Full Text]
  34. Donath S, Li P, Willenbockel C, Al-Saadi N, Gross V, Willnow T, et al. Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress. Circulation (2006) 113:1203–1212.[Abstract/Free Full Text]
  35. Nam YJ, Mani K, Ashton AW, Peng CF, Krishnamurthy B, Hayakawa Y, et al. Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Mol Cell (2004) 15:901–912.[CrossRef][Web of Science][Medline]
  36. Gustafsson AB, Tsai JG, Logue SE, Crow MT, Gottlieb RA. Apoptosis repressor with caspase recruitment domain protects against cell death by interfering with Bax activation. J Biol Chem (2004) 279:21233–21238.[Abstract/Free Full Text]
  37. Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC 3rd, Nunez G. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res (1999) 85:e70–e77.[Web of Science][Medline]
  38. Neuss M, Monticone R, Lundberg MS, Chesley AT, Fleck E, Crow MT. The apoptotic regulatory protein ARC (apoptosis repressor with caspase recruitment domain) prevents oxidant stress-mediated cell death by preserving mitochondrial function. J Biol Chem (2001) 276:33915–33922.[Abstract/Free Full Text]
  39. Takeuchi T, Ueki T, Nishimatsu H, Kajiwara T, Ishida T, Jishage K, et al. Accelerated rejection of Fas ligand-expressing heart grafts. J Immunol (1999) 162:518–522.[Abstract/Free Full Text]
  40. Jeremias I, Kupatt C, Martin-Villalba A, Habazettl H, Schenkel J, Boekstegers P, et al. Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia. Circulation (2000) 102:915–920.[Abstract/Free Full Text]
  41. Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo. Am J Physiol Heart Circ Physiol (2003) 284:H456–H463.[Abstract/Free Full Text]
  42. Djamali A, Odorico JS. Fas-mediated cytotoxicity is not required for rejection of murine nonvascularized heterotopic cardiac allografts. Transplantation (1998) 66:1793–1801.[CrossRef][Web of Science][Medline]
  43. Li Y, Takemura G, Kosai K, Takahashi T, Okada H, Miyata S, et al. Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure. Circ Res (2004) 95:627–636.[Abstract/Free Full Text]
  44. Gomez L, Chavanis N, Argaud L, Chalabreysse L, Gateau-Roesch O, Ninet J, et al. Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia-reperfusion. Am J Physiol Heart Circ Physiol (2005) 289:H2153–H2158.[Abstract/Free Full Text]
  45. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest (1996) 98:2854–2865.[Web of Science][Medline]
  46. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation (1997) 95:1247–1252.[Abstract/Free Full Text]
  47. Condorelli G, Morisco C, Latronico MV, Claudio PP, Dent P, Tsichlis P, et al. TNF-alpha signal transduction in rat neonatal cardiac myocytes: definition of pathways generating from the TNF-alpha receptor. FASEB J (2002) 16:1732–1737.[Abstract/Free Full Text]
  48. Janczewski AM, Kadokami T, Lemster B, Frye CS, McTiernan CF, Feldman AM. Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha. Am J Physiol Heart Circ Physiol (2003) 284:H960–H969.[Abstract/Free Full Text]
  49. Dibbs ZI, Diwan A, Nemoto S, DeFreitas G, Abdellatif M, Carabello BA, et al. Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype. Circulation (2003) 108:1002–1008.[Abstract/Free Full Text]
  50. Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA (2000) 97:5456–5461.[Abstract/Free Full Text]
  51. Sun M, Chen M, Dawood F, Zurawska U, Li JY, Parker T, et al. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation (2007) 115:1398–1407.[Abstract/Free Full Text]
  52. Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM, et al. Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res (2001) 89:709–715.[Abstract/Free Full Text]
  53. Rossig L, Hoffmann J, Hugel B, Mallat Z, Haase A, Freyssinet JM, et al. Vitamin C inhibits endothelial cell apoptosis in congestive heart failure. Circulation (2001) 104:2182–2187.[Abstract/Free Full Text]
  54. Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science (1998) 279:1954–1958.[Abstract/Free Full Text]
  55. Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity (1998) 9:267–276.[CrossRef][Web of Science][Medline]
  56. Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity (2000) 12:633–642.[CrossRef][Web of Science][Medline]
  57. Nelson DP, Setser E, Hall DG, Schwartz SM, Hewitt T, Klevitsky R, et al. Proinflammatory consequences of transgenic fas ligand expression in the heart. J Clin Invest (2000) 10:1199–1208.
  58. Wollert KC, 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]
  59. 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]

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



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
77/3/448    most recent
cvm074v3
cvm074v2
cvm074v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
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 ISI Web of Science
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 Sanchis, D.
Right arrow Articles by Comella, J. X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sanchis, D.
Right arrow Articles by Comella, J. X.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?