Cell Death and the Caspase Cascade
1998; Lippincott Williams & Wilkins; Volume: 97; Issue: 3 Linguagem: Inglês
10.1161/01.cir.97.3.227
ISSN1524-4539
Autores Tópico(s)Autophagy in Disease and Therapy
ResumoHomeCirculationVol. 97, No. 3Cell Death and the Caspase Cascade Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCell Death and the Caspase Cascade Stephen M. Schwartz Stephen M. SchwartzStephen M. Schwartz From the Department of Pathology, University of Washington, Seattle. Originally published27 Jan 1998https://doi.org/10.1161/01.CIR.97.3.227Circulation. 1998;97:227–229The article by Yaoita et al1 in this issue of Circulation is the first of what will indubitably be many articles on the role of the caspases in cell death. This is an important event. Until 10 years ago, we could not define death at all. Instead, we relied on the process of necrosis, the decay of the cell after its death, as a way to tell us that cells had died. Typical experiments involved applying a death stimulus for different time periods and then waiting hours or days to see if the death stimulus had effected a critical "point of no return."This point of view changed dramatically starting with the work of Horvitz in Caenorhabditis elegans. He defined three genes that made up a genetic pathway determining cell death in the nematode. These three genes were called ced-3, ced-4, and ced-9. ced-3 turned out to be a cysteine protease, that is, a protease with –SH in its active site instead of serine's –OH. Today we know that there are at least 10 caspases, the new name for cysteine proteases, and these form a cascade controlling death in most situations studied thus far.23The control of the caspases seems to depend on a simple principle: the enzymes are normally inactive as proforms. Activation requires proteolytic cleavage of the caspases at specific sites, and in most cases, these sites are themselves substrates for caspases. So, by analogy to coagulation, death is controlled by a cascade of proteases acting on each other.The promise of this as a therapeutic pathway emerges from two sources. First, a number of investigators, mainly in companies, have developed low-molecular-weight protease inhibitors. The specificity of these, as shown in the Figure, is still broad, but it is likely that more specific inhibitors will emerge. Second, we already know that there is an order to the pathway. For example, caspases 8 and 10 are "long-prodomain" activating caspases. They exert their activity on death not directly, but by interacting with specific receptors. These receptors include Fas and such Fas-related proteins as the tumor necrosis factor-1α receptor. It is likely that specific long-prodomain caspases will be found to interact with different death stimuli. Similarly, the caspases include short-prodomain caspases, eg, 3, 6, and 7. These seem to be the targets of the long-prodomain receptors and mediate the final proteolytic steps in the death pathway.45 Intriguingly, even knockouts in the effector caspases have a limited phenotype. This offers tremendous promise for our ability in the future to develop drugs appropriate to different kinds of death.Another reason for believing in the caspases as a likely therapeutic target is the recent evidence that cells not only have caspases, they also have proteins able to inhibit the caspases or prevent their activation. The serine protease coagulation and complement cascades are regulated by antiproteases, including proteases that digest and inactivate other proteases, allosteric modifiers of protease activity or irreversible protease substrates (serpins) that bind and inactivate enzymes. Examples of similar "anti-caspases" are now emerging for the caspases (Table).The simplest category of inhibitors may be substrates themselves. Tatsuta et al6 made the intriguing observation that cytoplasmic interleukin-1β (IL-1β), the prototypical substrate of the caspases, can act to inhibit Fas-mediated cell death. Although this might be an artifact of IL-1β secretion, it is worth considering the possibility that low levels of turnover of substrate regulate the activity of the low abundance, long-prodomain caspases and account for the need for activation of downstream caspases before death can occur.Another category of caspase inhibitors depends on the activation mechanism for the long-prodomain caspases. Caspases 8 and 10 are activated by interacting with a death adapter protein, FADD. FADD aggregates these "signaling" caspases onto the Fas receptor after the receptor aggregates as a result of interacting with its ligand. For example, sentrin is a protein that binds domains on Fas but not FADD. Sentrin may inhibit FADD-dependent death by preventing aggregation of FADD on activated Fas and secondarily inhibiting recruitment of caspase 8.7Like the coagulation enzymes, the caspases also appear to be regulated by serpins. Viral serpins that enhance viral survival by inhibiting caspases include p35, a general inhibitor of caspases by viruses in insect cells, and CrmA, produced by the cowpox virus in mammalian cells. Recently, an endogenous, nonviral serpin for the caspases has been identified in mammalian cells, proteinase inhibitor 9 (PI9). Sprecher and collaborators8 used serpin homology to clone PI9. Other members of this new family of nonsecreted, cytoplasmic serpins have been serine protease inhibitors910 ; however PI9 is a CrmA homolog. The selectivity of PI9 could be relevant to recent observations that different caspases, especially the long prodomain caspases including caspases 2, 8, 9, and 10, are involved in different types of cell death. Because PI9 can inhibit interleukin-1–converting enzyme (ICE), it is possible that it plays a role in inhibition of the ICE-like caspase believed to be required to activate mitochondria.11 Recently, Schonbeck et al12 reported an as-yet-unidentified protease inhibitor capable of blocking caspase 1 (ICE) in smooth muscle but not endothelial cytoplasm.The next category of caspase inhibitors, called IAPs, were also first recognized as viral proteins.13141516171819 Recently, however, mammalian IAPs have been recognized as well. Binding of IAPs to the TRAF molecules in the death receptor complexes suggested a role at the level of the initial activation of the long-prodomain caspases; however, a recent paper by Deveraux et al20 found that a mammalian X-linked IAP, XIAP, inhibited death by binding to caspases 3 and 7. Intriguingly, this effect was relatively specific for these terminal caspases. XIAP did not activate caspases 8, 6, or 1 even at 50-fold excess, at least against the substrate tested. This suggests that XIAP is an inhibitor of specific caspases. The mechanism of protease inhibition is not apparent, and it is not known whether this effect is limited to this one member of the IAP family.The final category of caspase inhibitors identified first in viruses are called "FLIPs." The FLIPs were recently discovered by Thome et al21 and Hu et al22 as viral proteins with homology to the DED of caspase 8 (FLICE). Death effector domains are the domains caspases use to aggregate to one another and to FADD. Like DED constructs of caspase 8,21 the viral FLIPs act as dominant negatives for FADD-mediated death apparently by acting as competitors for binding of the prodomains of caspase 8 or 10 and thus blocking Fas-mediated apoptosis. In recent months, eight different labs including our own have cloned cellular homologs of the FLIP gene.23 We called this cellular FLIP "MRIT." Intriguingly, MRIT abundance is very high in myocardium.Until this point, I have focused on the anticaspases as antiapoptotics. However, most readers are likely to be more familiar with another category of antiapoptotic genes, the "Bcl2" family. This is the same family as the ced-9 gene already referred to in my comments about Horvitz's work in C. elegans. Bcl2 members do control death, and ced-9 appears to be mainly antiapoptotic. The mechanism for this action is confusing because Bcl2 homologs can also stimulate cell death. The proapoptotic Bcl2 homologs are believed to possess this activity via their ability to increase mitochondrial permeability, releasing the cytochrome c. Bcl2 and its proapoptotic relatives seem to determine mitochondrial permeability by competing with each other in the formation of mitochondrial pores or perhaps by interacting with other molecules, including the mammalian ced-4, to control caspase activation (see below). Cytochrome c in turn activates a cytoplasmic molecule that we now know is the mammalian equivalent of Horvitz's third gene, ced-4. ced-4 functions, when complexed with cytochrome c, to activate the effector caspases.2425262728293031323334 In summary, we are beginning to see a central pathway of death that centers on the caspase cascade.In this regard, the article by Yaoita et al1 is likely to be the first of many exploring a new therapeutic direction. I would suggest there are three key areas to consider:1. Tissue specificity. The first generation of drugs are very nonspecific, and we know little about their possible toxicity, even in animals.2. Therapeutic efficacy. It is important to remember that caspases are not synonymous with death. Although death may be mediated in many situations by the effector caspases, it is likely that not all death occurs this way and equally likely that caspases play a role in cellular events in addition to death itself. An intriguing example of the latter may be the recent paper by Rodriguez et al.35 Normally, infusion of Fas-activating antibodies kills an animal because the liver is very sensitive to Fas activation. However, when these investigators protected the liver with an antiapoptotic transgene, the mice still died. The mice showed no morphological indication of apoptosis, raising the intriguing possibility that death may have occurred from a sublethal activation of the caspase pathway (at least, sublethal at the level of the individual cell).3. Finally, as seen in the article by Yaoita et al1 in this issue of Circulation, the protective effect of ZVAD-fmk was not total. Moreover, even the morphological evidence of an antiapoptotic effect, measured by the terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling assay, correlated poorly and was much more marked than the more functional measure of infarcted area. We do not know whether this is an issue of dose or an issue of the duration of injury versus the duration of drug.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Download figureDownload PowerPoint Figure 1. Classification of caspases. The shaded "U" encloses caspases believed to be the final mediators of death. Death may be initiated by receptors interacting with DED long-prodomain caspases and by mitochondria. Table 1. AnticaspasesCellularViralInteractionsSubstrates in excessInterleukin 1βCaspase 1DD competitorSentrinFas & TNF R DD domains, but not other DDCytoplasmic serpinsPAI-2Unknown proteasePI-9Caspase 1Crm A, p35, SPI-2caspase 1, caspase 3, caspase 8Caspase-binding inhibitorsc-IAPs X-IAPTRAFs, caspase 3, 7v-IAPDominant negative DED caspaseMRIT (aka CASPER, I-FLICE, c-FLIP) MRITCaspases, BCLx, BCLs, TRAFs, FADDv-FLIPFADD, DISC caspase 8TNF indicates tumor necrosis factor; PAI-2, plasminogen activator inhibitor-2.FootnotesCorrespondence to Stephen M. Schwartz, Department of Pathology, University of Washington, Box 357335, Seattle, WA 98195-7335. E-mail [email protected] References 1 Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation.1998; 97:276-281.CrossrefMedlineGoogle Scholar2 Xue D, Shaham S, Horvitz HR. The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev.1996; 10:1073–1083.CrossrefMedlineGoogle Scholar3 Alnemri ES. Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases. J Cell Biochem.1997; 64:33–42.CrossrefMedlineGoogle Scholar4 Nagata S. Apoptosis mediated by the Fas system. Prog Mol Subcell Biol.1996; 16:87–103.CrossrefMedlineGoogle Scholar5 Chinnaiyan AM, Dixit VM. Portrait of an executioner: the molecular mechanism of Fas/APO-1-induced apoptosis. Semin Immunol.1997; 9:69–76.CrossrefMedlineGoogle Scholar6 Tatsuta T, Cheng JH, Mountz JD. Intracellular IL- β is an inhibitor of Fas-mediated apoptosis. J Immunol.1996; 157:3949–3957.MedlineGoogle Scholar7 Okura T, Gong LM, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh E-TH. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J Immunol.1996; 157:4277–4281.MedlineGoogle Scholar8 Sprecher CA, Morgenstern KA, Mathewes S, Dahlen JR, Schrader SK, Foster DC, Kisiel W. Molecular cloning, expression, and partial characterization of two novel members of the ovalbumin family of serine proteinase inhibitors. J Biol Chem.1995; 270:29854–29861.CrossrefMedlineGoogle Scholar9 Dickinson JL, Bates EJ, Ferrante A, Antalis TM. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis: evidence for an alternate biological function. J Biol Chem.1995; 270:27894–27904.CrossrefMedlineGoogle Scholar10 Scott FL, Coughlin PB, Bird C, Cerruti L, Hayman JA, Bird P. Proteinase inhibitor 6 cannot be secreted, which suggests it is a new type of cellular serpin. J Biol Chem.1996; 271:1605–1612.CrossrefMedlineGoogle Scholar11 Castedo M, Hirsch T, Susin SA, Zamzami N, Marchetti P, Macho A, Kroemer G. Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis. J Immunol.1996; 157:512–521.MedlineGoogle Scholar12 Schonbeck U, Herzberg M, Petersen A, Wohlenberg C, Gerdes J, Flad HD, Loppnow H. Human vascular smooth muscle cells express interleukin-1 beta-converting enzyme (ICE), but inhibit processing of the interleukin-1 beta precursor by ICE. J Exp Med.1997; 185:1287–1294.CrossrefMedlineGoogle Scholar13 Duckett CS, Nava VE, Gedrich RW, Clem RJ, VanDongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J.1996; 15:2685–2694.CrossrefMedlineGoogle Scholar14 Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature.1996; 379:349–353.CrossrefMedlineGoogle Scholar15 Manji GA, Hozak RR, LaCount DJ, Friesen PD. Baculovirus inhibitor of apoptosis functions at or upstream of the apoptotic suppressor P35 to prevent programmed cell death. J Virol.1997; 71:4509–4516.CrossrefMedlineGoogle Scholar16 Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci U S A.1996; 93:4974–4978.CrossrefMedlineGoogle Scholar17 Clem RJ, Duckett CS. The iap genes: unique arbitrators of cell death. Trends Cell Biol.1997; 7:337–339.Google Scholar18 Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med.1997; 3:917–921.CrossrefMedlineGoogle Scholar19 Irmler M, Thome M, Hahne M, Schneider P, Hofmann B, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP. Nature.1997; 388:190–195.CrossrefMedlineGoogle Scholar20 Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature.1997; 388:300–304.CrossrefMedlineGoogle Scholar21 Thome M, Schneider P, Hofman K, Fickenscher H, Meinl E, Neipel F, Mattman C, Burns K, Bodmer J-L, Schroeter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J. Viral FILICE-inhibitory proteins (FLIPS) prevent apoptosis induced by death receptors. Nature.1997; 386:517–521.CrossrefMedlineGoogle Scholar22 Hu S, Vincenz C, Buller M, Dixit VM. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J Biol Chem.1997; 272:9621–9624.CrossrefMedlineGoogle Scholar23 Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RD, Baskin DG, Schwartz SM, Hood L. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXl and initiates death. Proc Natl Acad Sci U S A.1997; 94:11333-11338.CrossrefMedlineGoogle Scholar24 Armstrong RC, Aja T, Xiang J, Gaur S, Krebs JF, Hoang K, Bai X, Korsmeyer SJ, Karanewsky DS, Fritz LC, Tomaselli KJ. Fas-induced activation of the cell death-related protease CPP32 is inhibited by Bcl-2 and by ICE family protease inhibitors. J Biol Chem.1996; 271:16850–16855.CrossrefMedlineGoogle Scholar25 Korsmeyer SJ. Regulators of cell death. Trends Genet.1995; 11:101–105.CrossrefMedlineGoogle Scholar26 Yin XM, Oltvai ZN, Korsmeyer SJ. Heterodimerization with Bax is required for Bcl-2 to repress cell death. Curr Top Microbiol Immunol.1996; 194:331–338.Google Scholar27 Yin XM, Oltvai ZN, Veis-Novack DJ, Linette GP, Korsmeyer SJ. Bcl-2 gene family and the regulation of programmed cell death. Cold Spring Harb Symp Quant Biol.1996; 59:387–393.Google Scholar28 Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood.1996; 88:386–401.CrossrefMedlineGoogle Scholar29 Yang J, Liu XS, Bhalla K, Kim CN, Ibrado AM, Cai JY, Peng TI, Jones DP, Wang XD. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science.1997; 275:1129–1132.CrossrefMedlineGoogle Scholar30 Shimizu S, Eguchi Y, Kamiike W, Matsuda H, Tsujimoto Y. Bcl-2 expression prevents activation of the ICE protease cascade. Oncogene.1996; 12:2251–2257.MedlineGoogle Scholar31 Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, Fassy F, Reed JC, Kroemer G. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med.1997; 186:25–37.CrossrefMedlineGoogle Scholar32 Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, Geuskens M, Kroemer G. The apoptosis-necrosis paradox: apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene.1997; 15:1573–1581.CrossrefMedlineGoogle Scholar33 Kroemer G. Mitochondrial implication in apoptosis: towards an endosymbiont hypothesis of apoptosis evolution. Cell Death Differ.1997; 4:443–456.CrossrefMedlineGoogle Scholar34 Marchetti P, Hirsch T, Zamzami N, Castedo M, Decaudin D, Susin SA, Masse B, Kroemer G. Mitochondrial permeability transition triggers lymphocyte apoptosis. J Immunol.1996; 157:4830–4836.MedlineGoogle Scholar35 Rodriguez I, Matsuura K, Khatib K, Reed JC, Nagata S, Vassalli P. A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. J Exp Med.1996; 183:1031–1036.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Goeden N and Bonnin A (2014) Ex vivo Perfusion of the Mouse Placenta for Maternal–Fetal Interaction Studies during Pregnancy The Guide to Investigation of Mouse Pregnancy, 10.1016/B978-0-12-394445-0.00057-6, (661-671), . Wang R, Zhang T, Xu Z, Hu K, Shi Y, Long S and Yue H (2014) Injury in Minipig Parotid Glands following Fractionated Exposure to 30 Gy of Ionizing Radiation, Otolaryngology–Head and Neck Surgery, 10.1177/0194599814528103, 151:1, (100-106), Online publication date: 1-Jul-2014. Goeden N and Bonnin A (2012) Ex vivo perfusion of mid-to-late-gestation mouse placenta for maternal-fetal interaction studies during pregnancy, Nature Protocols, 10.1038/nprot.2012.144, 8:1, (66-74), Online publication date: 1-Jan-2013. Joshi G and Knecht D (2013) Silica phagocytosis causes apoptosis and necrosis by different temporal and molecular pathways in alveolar macrophages, Apoptosis, 10.1007/s10495-012-0798-y, 18:3, (271-285), Online publication date: 1-Mar-2013. Yang D, Lai D, Huang X, Shi X, Gao Z, Huang F, Zhou X and Geng Y (2012) The defects in development and apoptosis of cardiomyocytes in mice lacking the transcriptional factor Pax-8, International Journal of Cardiology, 10.1016/j.ijcard.2010.08.057, 154:1, (43-51), Online publication date: 1-Jan-2012. Sun Z, Ling M, Huo Y, Chang Y, Li Y, Qin H, Yang G and Lucas R (2010) Caspase 9 gene polymorphism and susceptibility to lumbar disc disease in the Han population in northern China, Connective Tissue Research, 10.3109/03008207.2010.510914, 52:3, (198-202), Online publication date: 1-Jun-2011. Takahashi K, Ohyabu Y, Schaffer S and Azuma J (2010) Cellular characterization of an in-vitro cell culture model of seal-induced cardiac ischaemia, Journal of Pharmacy and Pharmacology, 10.1211/0022357011775433, 53:3, (379-386), Online publication date: 18-Feb-2010. Ahmed B (2008) Exercise as a neuroprotective mechanism in Parkinson's disease: Future treatment potential?, British Journal of Neuroscience Nursing, 10.12968/bjnn.2008.4.11.31691, 4:11, (525-530), Online publication date: 1-Nov-2008. (2006) Apoptosis: molecular mechanisms in hypertension Molecular Mechanisms in Hypertension, 10.1201/b14627-37, (290-305) Hughes S (2003) Detection of apoptosis usingin situ markers for DNA strand breaks in the failing human heart. Fact or epiphenomenon?, The Journal of Pathology, 10.1002/path.1447, 201:2, (181-186), Online publication date: 1-Oct-2003. Moe G, Naik G, Konig A, Lu X and Feng Q (2002) Early and persistent activation of myocardial apoptosis, bax and caspases: insights into mechanisms of progression of heart failure, Pathophysiology, 10.1016/S0928-4680(02)00008-1, 8:3, (183-192), Online publication date: 1-Jun-2002. Barton M and Kockx M (2002) Estrogen and apoptosis in atherosclerosis, International Congress Series, 10.1016/S0531-5131(01)00466-6, 1229, (81-93), Online publication date: 1-Feb-2002. Francis G (2001) Pathophysiology of chronic heart failure, The American Journal of Medicine, 10.1016/S0002-9343(98)00385-4, 110:7, (37-46), Online publication date: 1-May-2001. Brancato R, Schiavone N, Siano S, Lapucci A, Papucci L, Donnini M, Formigli L, Orlandini S, Carella G, Carones F and Capaccioli S (2018) Prevention of Corneal Keratocyte Apoptosis after Argon Fluoride Excimer Laser Irradiation with the Free Radical Scavenger Ubiquinone Q10, European Journal of Ophthalmology, 10.1177/112067210001000106, 10:1, (32-38), Online publication date: 1-Jan-2000. Farina F, Cappello F, Todaro M, Bucchieri F, Peri G, Zummo G and Stassi G (2000) Involvement of Caspase-3 and GD3 Ganglioside in Ceramide-induced Apoptosis in Farber Disease, Journal of Histochemistry & Cytochemistry, 10.1177/002215540004800106, 48:1, (57-62), Online publication date: 1-Jan-2000. Chung E, Choi S, Shim Y, Bang Y, Hur K and Kim C (2000) Transforming Growth Factor-β Induces Apoptosis in Activated Murine T Cells through the Activation of Caspase 1-like Protease, Cellular Immunology, 10.1006/cimm.2000.1694, 204:1, (46-54), Online publication date: 1-Aug-2000. Pohlman T and Harlan J (2000) Adaptive Responses of the Endothelium to Stress, Journal of Surgical Research, 10.1006/jsre.1999.5801, 89:1, (85-119), Online publication date: 1-Mar-2000. Vaquero M (2000) Apoptosis: ser o no ser, ésa es la cuestión, Medicina Clínica, 10.1016/S0025-7753(00)71222-X, 114:4, (144-156), Online publication date: 1-Jan-2000. Holtz J, Tostlebe M and Darmer D (2000) Mechanisms and relevance of apoptosis Molecular Approaches to Heart Failure Therapy, 10.1007/978-3-642-57710-9_15, (197-231), . Denner L (2005) Caspases in apoptotic death, Expert Opinion on Investigational Drugs, 10.1517/13543784.8.1.37, 8:1, (37-50), Online publication date: 1-Jan-1999. Yeh E (2015) Life and Death of the Cell, Hospital Practice, 10.3810/hp.1998.08.104, 33:8, (85-92), Online publication date: 15-Aug-1998. January 27, 1998Vol 97, Issue 3 Advertisement Article InformationMetrics Copyright © 1998 by American Heart Associationhttps://doi.org/10.1161/01.CIR.97.3.227 Originally publishedJanuary 27, 1998 KeywordsproteinsEditorialscellsapoptosisPDF download Advertisement
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