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(Circulation. 1997;95:782-786.)
© 1997 American Heart Association, Inc.

Articles

Life and Death in the Cardiovascular System

Edward T.H. Yeh, MD

the Divisions of Molecular Medicine and Cardiology, Department of Internal Medicine, and Cardiovascular Research Center, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas–Houston Health Science Center.

Correspondence to Edward T.H. Yeh, MD, Division of Molecular Medicine, University of Texas–Houston Health Science Center, 6431 Fannin, Suite 4200, Houston, TX 77030.

Key Words: Editorials • apoptosis • free radicals • molecular biology

	Introduction

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
There is a time for everything, and a season for every activity under heaven: A time to be born and a time to die.

Ecclesiastes 3:2

In recent years, the concept of apoptosis¹ has swept through the fields of biology and medicine, creating a cultlike following in many disciplines, including cardiovascular research. This editorial is written explicitly to update the readers of Circulation on this fascinating and rapidly expanding field. The focus is on the concept of apoptosis relevant to cardiovascular diseases. Not all of the research areas in apoptosis can be covered in great depth in this editorial. Interested readers should consult several other excellent reviews for details.^{2 3 4 5 6 7 8 9 10 11}

	Apoptosis: Definition and Detection

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
The word apoptosis was derived from Greek, meaning falling off of petals from a flower.¹ A professor of Greek suggested this usage to his pathology colleagues at the University of Aberdeen, Scotland, in the early 1970s to describe a form of cell death with distinct morphological features that was not widely recognized at that time. As shown in Fig 1A, when a cell receives the signal to die an apoptotic death, it goes through a series of morphological changes that can be easily observed with the light microscope. Starting from shrinkage of cell membrane, to condensation of nuclear chromatin, to cellular fragmentation, to the engulfment of the apoptotic bodies by neighboring cells, apoptotic death follows a carefully orchestrated script.

View larger version (129K): [in this window] [in a new window]   Figure 1. A, Morphological changes characteristic of apoptosis. Cell receives death signal and undergoes apoptosis. Fragmented bodies are taken up by neighboring cell. B, Fas signaling pathway. Fas ligand (FasL) causes aggregation of Fas molecules, which initiate recruitment of FADD and FLICE to complex. For simplicity, only one molecule each of FADD and FLICE are depicted. D denotes death domain; E, death-effector domain; I, ICE-like domain. Cytoplasmic domain of Fas molecule contains a death domain (D). FADD is composed of a death domain and a death-effector domain (E). FLICE is composed of a death-effector domain and an ICE-like domain. Death domain can interact with death domain; death-effector domain can interact with another death-effector domain. FADD is also called MORT1; FLICE is also called MACH. Red cross indicates death. C, Hypothetical model of apoptosis signaling. B denotes good members of Bcl-2 family drawn as a dimer; C, cytochrome c; ICE/CED3, members of protease family.

Although the term apoptosis was introduced only 30 years ago, typical apoptotic morphology has been described by others as far back as the late 1880s.⁵ Early scholars recognized the need for some mechanism to counterbalance cellular proliferation, especially during the development of organs. For example, during development of the limb, cells in the interdigital zone undergo massive apoptotic death to allow for formation of the shape of digits. These cells are obviously programmed to die, and their deaths are considered a normal physiological process. If the interdigital cells do not die, webbed toes or fingers will be the unsightly result. Apoptosis, however, is not limited to cell death during embryonic development. In recent years, apoptosis has been implicated in cell deaths caused by ionized radiation, steroid treatment, chemotherapy, and ischemia-reperfusion injury.³

The initial description of apoptosis was based on morphological features (Fig 1A). Several useful biochemical and immunohistochemical detection methods were proposed later. Andrew Wyllie¹² described fragmentation of nuclear DNA into multiples of 180 bp as the result of endogenous endonuclease activation in a classic paper published in 1980. When fragmented DNAs were electrophoresed in an agarose gel, they separated into a characteristic DNA ladder pattern. Gavrieli et al¹³ described another widely used method in which DNA breaks in apoptotic cells were marked by dUTP-biotin transferred to the free 3'-end of cleaved DNA. Because terminal deoxynucleotidyl transferase was used to transfer dUTP-biotin by nick end-labeling, a more convenient acronym, TUNEL, was used to describe this procedure. Examples of TUNEL staining are shown in the article by Perlman et al in this issue of Circulation.¹⁴

	More Than One Way to Die: Apoptosis Versus Necrosis

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
Apoptosis should be contrasted to necrosis, which is characterized by swelling of cells, breakdown of membrane barrier, and random degradation of nuclear DNAs and is often accompanied by intense inflammatory response. The classic example of necrosis is ischemic necrosis of the cardiomyocyte in acute myocardial infarction. Thus, necrosis is considered a nonphysiological form of cell death. Others call necrosis death by murder, contrasting with the concept of death by suicide in apoptosis. This concept is not generally useful because in many instances, cells are murdered either by cytotoxic T cells or by other toxic substances via the classic apoptotic program shown in Fig 1A.

The main differences between apoptosis and necrosis are listed in the Table. The distinction between apoptosis and necrosis should be self-evident at a quick glance. However, there are gray areas in which the distinction may not be clear. Readers interested in the classification of cell death mechanisms and terminology should consult the excellent review by Majno and Joris.⁵

View this table: [in this window] [in a new window]   Table 1. Apoptosis Versus Necrosis

	Genetics of Apoptosis: Of Worm and Man

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
Apoptosis is often equated with programmed cell death, which implies a genetic master plan that dictates cell fate. The influence of genetics is best illustrated by the lessons learned from the hermaphrodite nematode worm Caenorhabditis elegans.¹⁵ Of the 1090 cells produced by the worm during development, 131 are destined to die. A large number of mutations affecting the development of this organism have been identified and their corresponding genes cloned. These genes can be divided into four groups: those affecting the decision to die, the execution of death, the engulfment of the dead cells, and the degradation of engulfed bodies. One of the genes is called ced-3 (ced stands for cell death defective). This gene is involved in the execution of the death program, because recessive mutations of ced-3 prevent the cell death that normally occurs during C elegans development.¹⁶ The ced-3 gene product belongs to the family of interleukin-1ß–converting enzyme (ICE), which contains a number of cysteine proteases that play critical roles in the execution of the cell death program (see below). Another gene, ced-9, is required to protect cells that should have survived from undergoing programmed cell death.¹⁷ The human homologue of ced-9 is Bcl-2, which also plays the role of protector in mammalian apoptosis (see below). Thus, the genetic control of apoptosis is highly conserved throughout evolution.

	Assembly of the Death Complex: Fas Signaling as a Paradigm

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
In this issue of Circulation, Perlman et al¹⁴ show that balloon injury could induce rapid onset of apoptosis in medial smooth muscle cells. The biochemical mechanism responsible for initiation of apoptosis after balloon injury cannot be readily discerned. In a recent review, more than 30 inducers of apoptosis have been listed, ranging from tumor necrosis factor (TNF) to ß-amyloid peptides.³ It is not possible to review all the potential signaling mechanisms leading to apoptosis after these triggers. Here, I will use the Fas signaling pathway as a paradigm to illustrate a better-defined pathway of apoptosis signaling.

Fas, also called APO-1, is a member of the TNF receptor (TNFR) family.⁷ Fas and TNFR1 share a common cytoplasmic signaling motif called the death domain. Deletion or mutation in the death domain abolishes the ability of these receptors to transduce apoptosis signal. Because the death domain does not contain any obvious kinase or phosphatase motif, its signaling function must be dependent on other associated proteins.

As shown in Fig 1B, Fas signals by assembling a complex that contains Fas and at least two other molecules: FADD and FLICE. FADD contains a cell death domain (D) in the C-terminus and uses it to interact with the death domain of Fas.¹⁸ The N-terminus of FADD contains another novel motif, called the death-effector domain (E), which is used for binding to the third protein, FLICE. FLICE and FADD interact via their respective death-effector domains. Thus, FADD is simply an adapter molecule that serves to recruit FLICE to the complex. Most interestingly, FLICE contains an ICE-like domain (I) that may function as an initiator of the cysteine protease cascade.¹⁰ Both FADD and FLICE have also been shown to play a critical role in TNF-induced apoptosis. However, another adapter molecule, TRADD, is needed to recruit FADD to the death domain of TNFR1. The elegant apoptosis signaling pathway of Fas and TNFR1 was discovered only very recently, demonstrating the rapid progress of our understanding of the biochemistry of apoptosis. Currently, we do not know whether other apoptosis triggers also use similar signaling pathways.

	Executioners: The ICE Family

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
It is remarkable that Fas- and TNFR1-mediated apoptosis converges on FLICE, a member of the ICE-related cysteine proteases. At least nine homologous proteases belong to the ICE family.¹⁰ They can be divided into three subfamilies: (1) the Ced-3–like subfamily, including CPP32ß (also known as Yama and apopain), FLICE, Mch2, Mch3 (also known as ICE–LAP-3 and CMH-1), and Mch4; (2) the ICE subfamily, including ICE, ICE relI (also known as Tx and ICH2), and ICE rel III; and (3) the NEDD-2 subfamily, including ICH-1 and Nedd-2. The ICE family members, unlike other mammalian cysteine proteases, cleave their substrates after an aspartate residue at the P1 position. They exist in the cytosol as proenzymes that require accurate processing at internal aspartate residues to generate the two-chain active enzymes. A large number of cellular targets for these cysteine proteases have been reported. They include actin, nuclear laminin, protein kinase C, poly(ADP-ribose) polymerase, and U1 ribonuclear protein.⁹ The linkage between the substrate specificity and morphological changes has not been established. However, members of the ICE family clearly play a central role in setting up a proteolytic state that commits the cell to die.

Some ICE family members can also activate themselves or each other in a manner similar to the protease proenzymes of the coagulation or complement cascades. The order in which the ICE family members activate each other either sequentially or in combination in vivo has not been clearly elucidated. Overexpression of several members of the ICE family in cell lines leads to morphological changes in the nucleus typical of apoptosis.¹⁰ Prevention of accidental activation of the ICE family is essential for survival. Two viral gene products, p35 derived from baculovirus and CrmA derived from the cowpox virus, are potent inhibitors of some of the ICE family members. Both CrmA and p35 are capable of blocking anti-Fas– and TNF-induced apoptosis. Cell-permeable peptide inhibitors have also been shown to be effective blockers of in vivo ICE activities.¹⁹ Regulation of the ICE family members is currently under intense investigation because of their potential as drug targets.

	Guardian Angels: The Bcl-2 Family

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
Bcl-2 was originally identified as the t(14;18) breakpoint in follicular B-cell lymphoma.⁸ Like the ICE family members, Bcl-2 also belongs to an extended family. They can generally be divided into the prolife members, such as Bcl-2, Bcl-x, and Mcl-1, and the prodeath members, such as Bax and Bad.²⁰ These proteins appear to dimerize with themselves and each other through the Bcl-2 homology domains.²¹ Thus, the relative balance of the prolife versus the prodeath dimers may determine the susceptibility of the cell to apoptosis induction.^{20 22} The mechanism of action of the Bcl-2 family has not been clearly elucidated. Some of the family members, such as Bcl-2, Bcl-x, and Mcl-1, contain a lipid-anchoring domain in their C-termini that may be important for targeting to the mitochondria or endoplasmic reticulum membrane.²¹ This is consistent with the immunolocalization of Bcl-2 to the mitochondria, endoplasmic reticulum, and nuclear membrane. Recently, x-ray crystallography showed the structure of Bcl-x_L to be similar to that of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins.²³ Thus, the Bcl-2 family could function to protect membrane integrity.²⁴ However, the final words on its mechanism of action remain to be written.

The importance of Bcl-2 and Bcl-x in normal physiology is best illustrated by mice that are deficient in these proteins. Bcl-2–deficient mice developed fulminant lymphoid apoptosis, hypopigmented hair, and polycystic kidney.²⁵ Bcl-x–deficient mice died around embryonic day 13. Massive cell death of immature hematopoietic cells and neurons occurred in the Bcl-x–deficient mice.²⁶ A large body of literature is available on the protective effect of Bcl-2 or Bcl-x overexpression on the susceptibility of different cell lines to various apoptosis-inducing signals. However, inconsistencies also exist. For example, Bcl-2 protects against anti-Fas–induced apoptosis in some systems but not others. The variable protective effect may be the result of other prolife or prodeath factors operative at a given cell.

The Bcl-2 family members are also subject to transcription regulation. The tumor suppressor p53 has been shown to be a direct transcriptional activator of the human bax gene.²⁷ The induction of bax message by p53 is consistent with the role of P53 in some forms of apoptosis. In this issue of Circulation, Perlman et al¹⁴ show that the Bcl-x protein level in the medial smooth muscle cells dramatically diminished after balloon injury. The mechanism leading to lower Bcl-x levels in the medial smooth muscle cells, however, has not been elucidated.

	Coconspirator: The Mitochondria

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
The story on apoptosis is not complete without some discussion about the role of mitochondria. As noted in a recent commentary,²⁸ the involvement of mitochondria in apoptosis has been in and out of fashion. The mitochondria are a source of reactive oxygen species, which were thought to be involved in apoptosis induction. This hypothesis was supported by the protective effect of manganous superoxide dismutase in TNF-induced cell death. The protective effect of Bcl-2 was also thought to be due to its antioxidant function.²⁹ However, contradictory evidence also abounds. In cell lines that are deficient in mitochondrial respiration, Bcl-2 still protects against apoptosis induction.³⁰ A recent article points out that reduction in mitochondrial potential constitutes an early, irreversible step of programmed lymphocyte death in vivo that is due to the opening of mitochondrial permeability transition pores.²⁴ Furthermore, mitochondria may contribute to apoptosis not by releasing reactive oxygen species but by releasing a heat-labile protein.²⁴ A separate study shows that cytochrome c was released from mitochondria and was able to induce apoptosis in a cell-free system.³¹ Cytochrome c may be involved in the activation of CPP32, a member of the ICE family.³¹ At present, the signal(s) that cause the opening of the mitochondrial permeability transition pores still remain elusive.

	Integration of the Apoptosis Pathways

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
The biochemistry of apoptosis signaling is clearly very complex. The major players were briefly introduced above. How can we make sense of these complicated scripts with a cast of thousands? I will attempt to integrate the apoptosis pathway from three levels of complexity.

The simplest model is shown in Fig 1B, in which apoptosis signaling through Fas can be accomplished through a three-step process: (1) aggregation of the Fas molecule, (2) recruitment of FADD, and (3) recruitment and activation of FLICE. Activation of FLICE would then lead to activation of the protease cascade and commit the cell to die. Fas signaling could represent a special case in which the Bcl-2 family and mitochondria are not directly involved in apoptosis induction. However, this model probably cannot be generalized to all cases of Fas-mediated apoptosis.

A more complex model is shown in Fig 1C, in which death signals are delivered to the mitochondria, which is protected by the good members of the Bcl-2 family. However, if the death signals are overwhelming, mitochondrial damage will result and cytochrome c will be released. Cytochrome c plus additional cytosolic factors then initiate the cysteine protease cascade. This model incorporates some of the newer information about apoptosis signal and includes both the Bcl-2 family and mitochondria in the scheme.

The scheme proposed in Fig 1C does not take into account a large number of newly discovered genes^{32 33 34} or second messenger systems that may also regulate apoptosis. It is not plausible to place all of these newcomers into the pathway. Several generalizations, however, can be made regarding additional inputs into the system. For example, the mitogen-activated protein (MAP) kinase pathway and the stress-activated kinase pathway appear to have opposing effects in apoptosis signaling. Activation of the MAP kinase pathways prolongs survival, whereas activation of the stress-activated kinase pathways promotes cell death.³⁵ Ceramide promotes cell death, whereas sphingosine 1-phosphate opposes it.³⁶ These modulating signals may feed into different parts of the pathway. In addition, transcription factors, through their effects on gene regulation and cell cycle regulation, could also affect the apoptotic pathway.¹¹

	Life Lessons to Be Learned From Death

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
Apoptosis, despite its deadly nature, has become a highly fashionable and competitive area of research. Fortunately, it has not escaped the attention of the cardiovascular community. Sightings of apoptosis have been reported from every corner of cardiovascular medicine, ranging from restenosis to conduction system defects to congestive heart failure.^{37 38 39 40 41 42} There is no question that these sightings will eventually be converted into mechanistic insights and will form the basis for designing new diagnostic modalities and novel therapies.

	Acknowledgments

 
This work was supported in part by National Institutes of Health grant HL-45851 and an Established Investigator Award from the American Heart Association to Dr Yeh.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Apoptosis: Definition and... More Than One Way... Genetics of Apoptosis: Of... Assembly of the Death... Executioners: The ICE Family Guardian Angels: The Bcl-2... Coconspirator: The Mitochondria Integration of the Apoptosis... Life Lessons to Be... References

 
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