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(Circulation Research. 1997;81:137-144.)
© 1997 American Heart Association, Inc.

Articles

Death by Design

Programmed Cell Death in Cardiovascular Biology and Disease

W. Robb MacLellan, , Michael D. Schneider

From the Molecular Cardiology Unit (W.R.M., M.D.S.), the Departments of Medicine (W.R.M.), Cell Biology (M.D.S.), and Molecular Physiology & Biophysics (M.D.S.), and Houston Veterans Affairs Medical Center (W.R.M.), Baylor College of Medicine, Houston, Tex.

Correspondence to Michael D. Schneider, MD, Molecular Cardiology Unit, Baylor College of Medicine, One Baylor Plaza, Room 506C, Houston, TX 77030. E-mail michaels{at}bcm.tmc.edu

	Abstract

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
Abstract Programmed cell death (apoptosis) is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, and long-standing heart failure. Although the exact mechanisms initiating apoptosis in these in vivo settings remain unproven, insights into the molecular circuitry controlling apoptosis more widely suggest the potential to protect mammalian ventricular muscle from apoptosis through one or more of these pathways, by pharmacological means or, conceivably, gene transfer.

Key Words: apoptosis • gene transfer • heart failure • ischemia

	Introduction

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
Cardiovascular researchers and clinicians have long been intrigued by the observation that myocyte cell loss in the absence of identifiable necrosis accompanies many forms of myocardial disease and even normal aging.^{1 2 3} However, rational explanations for this phenomenon have been lacking until recently. Twenty years ago, investigators described a novel form of cell death distinct from necrosis, designated apoptosis.⁴ In contrast to the classic swelling and membrane rupture associated with necrosis, apoptotic cells shrank and maintained their membrane integrity. Hallmarks of apoptosis include cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation. Apoptotic cells are phagocytosed by neighboring cells, effectively removing unwanted cells without an inflammatory response. Since these pivotal observations were made, it has been recognized increasingly that programmed cell death (apoptosis) plays a critical role in both the normal development and the pathology of a wide variety of tissues.^{5 6} For example, normal physiological apoptosis occurs during thymic involution⁷ or removal of autoreactive lymphocytes during development⁸ ; however, inappropriate apoptosis may contribute to neurodegenerative diseases^{9 10} or acquired immunodeficiency syndrome.¹¹

Investigations of apoptosis in the context of heart disease have been accelerated by extensive progress in the molecular biology of apoptosis more generally, with the identification of specific genes controlling this form of cell death. Programmed cell death is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, vascular wall remodeling, and long-standing heart failure. Apoptosis has been the subject of several recent general reviews.^{5 6 12 13 14} In the present article, we will examine the current status of knowledge regarding apoptosis as it pertains to the cardiovascular system, specifically.

	Apoptosis in Normal Cardiac Development

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
An essential role for programmed cell death during development first was suggested from studies of the nematode Caenorhabditis elegans, where activation of programmed cell death is necessary for normal remodeling and morphogenesis.¹⁵ In mammals, analogously, focal apoptosis is responsible for elimination of interdigital webs¹⁶ and, in males, for regression of the müllerian tube.¹⁷ As in the development of many other organ systems, this form of cell death also may play a critical role in cardiac organogenesis. Despite long-standing morphological evidence of cell death in the conotruncal cushions, which mediates remodeling of the bulbus cordis,¹⁸ only recently has it been appreciated that this comprises apoptosis.¹⁹ In this context, apoptosis also involves the atrioventricular cushions, to a lesser extent, and peaks at 13 to 14 days of gestation in the mouse (E. Fernandez and R. Shohet, unpublished data, 1996).

It has been suggested that cell death during postnatal morphogenesis in the atrioventricular node and His bundle might occur through apoptosis, with the potential that aberrations in this process could predispose to tachyarrhythmias or bradyarrhythmias in adulthood.²⁰ Notably, preferential apoptosis within the right ventricle has been postulated as an explanation for the observed differences in myocyte number and chamber mass that accompany the transition from a fetal to an adult circulatory system.²¹ This propensity of the right ventricular myocardium to undergo apoptosis also correlated with reduced expression of the anti-apoptotic gene, Bcl-2. As other critical steps during cardiac morphogenesis are reexamined in the light of increased knowledge concerning mechanisms for programmed cell death and given the improved technologies to identify this event, it is foreseeable that recognition of the importance of apoptosis in cardiac morphogenesis will only increase.

	Apoptosis Occurs With Reperfusion Injury, End-Stage Heart Failure, and Other Cardiac Disorders

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
The possibility that myocyte death in cardiac disease might occur, even in part, by programmed cell death rather than necrosis has been considered only recently,^{20 22 23} although potential clues existed, such as the finding of scattered myocyte death during ventricular remodeling,¹ dilated cardiomyopathy,² and senescence.³ Evidence for apoptosis has accumulated rapidly in the past 2 to 3 years, prompted by landmark studies documenting apoptosis of cardiac myocytes subjected to hypoxia in culture²⁴ and of intact cardiac muscle after ischemia and reperfusion in vivo.²⁵ The pathophysiological contexts in which cardiac muscle apoptosis has been documented now also include myocardial infarction,^{26 27} heart failure induced by rapid ventricular pacing^{28 29} or coronary microemboli,³⁰ several models of pressure-overload hypertrophy (passive load of isolated papillary muscles,¹ aortic banding,³¹ and genetically determined hypertension in rats and mice³² ), and overexpression of G_s in transgenic mice.³³

Furthermore, apoptotic cell death also has been identified in human atherosclerosis,^{34 35} atherectomy specimens,³⁶ and saphenous vein grafts.³⁷ Areas of greatest apoptosis were localized to the vascular smooth muscle cells subjacent to the endothelium,³⁵ suggesting a possible role in destabilizing the plaque and promoting rupture. Programmed cell death in vascular smooth muscle was colocalized with the expression of ICE (CASP-1), whose functional role in apoptosis is discussed below.³⁴ Although specific triggers for apoptosis in the vessel wall are unknown, it has been suggested that NO promotes apoptosis in vascular smooth muscle cells³⁸ and infiltrating monocytes.³⁵ Whereas NO bioactivity is reportedly reduced in the vessel wall in hypercholesteremia, administration of the NO precursor L-arginine inhibited atherogenesis in hypercholesteremic rabbits,³⁹ with regression of preexisting lesions.⁴⁰ This may be the first example of modulating apoptosis to achieve a therapeutic benefit in vascular disease.

With regard to myocardial ischemia, apoptosis may be the predominant form of cell death early after coronary artery ligation in the rat, followed by necrosis at later time points²⁷ ; eg, apoptosis affected 2.8x10⁶ cells and necrosis affected only 90 000 myocytes at 2 hours. In addition, apoptosis may contribute to delayed myocyte loss after infarction, at least in this species, peaking at 7 days, in parallel with cell cycle reentry measured by proliferating cell nuclear antigen–positive cells.⁴¹ Apoptosis has been substantiated during myocardial infarction in humans as well, affecting at least 12% of myocytes in the peri-infarct border zone and 1% of the distant myocardium⁴² (see also References 26 and 43^{26 43} ). Especially striking are recent estimates for the remarkable extent of apoptosis after 20 minutes of ischemia and 24 hours of reperfusion in the rat (62±5% of myocytes versus little in nonischemic sections or sham-operated hearts).⁴⁴ Higher than expected frequencies for apoptosis, where based only on in situ labeling of nicked DNA, should raise two concerns: the a priori potential for false-positive results and the further possibility that excessive reliance on this in situ method might fail to discriminate between apoptosis and necrosis with absolute certainty.

Coronary artery ligation also induced marked upregulation of Bcl-2 and Fas in cardiac myocytes,²⁷ two genes whose functional involvement in apoptosis will be discussed below. Fas induction likewise was associated with apoptosis of cardiac myocytes in the hypoxia,²⁴ passive stretch,¹ and pacing²⁹ studies already cited, and plasma levels of the soluble Fas fragment are increased progressively in patients with New York Heart Association class II to IV heart failure.⁴⁵ However, a causal relationship between apoptosis and these genes in cardiac muscle remains to be determined.

	Inducers of Apoptosis in the Heart and Vasculature

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
Although increasing descriptive evidence thus suggests that apoptosis occurs in many cardiovascular disorders, as well as in normal organogenesis, it is less clear what the relevant physiological triggers might be. Control of programmed cell death is dependent on a balance between inhibitors and inducers of apoptosis. Oxidative stress, calcium overload, mitochondrial defects, stimulation by proapoptotic factors, or loss of cardiac myocyte survival factors each could, theoretically, result in apoptosis. We will focus on the potential factors capable of inducing apoptosis in cardiac muscle, for which the most direct evidence now exists.

Reactive oxygen species are a principal mediator of cell damage in diverse pathological conditions. Many agents used to induce apoptosis also produce oxygen radicals and are inhibited by antioxidants.^{46 47} The mechanism by which oxygen radicals might induce apoptosis is incompletely understood; however, since free radicals induce DNA damage with concomitant upregulation of p53,⁴⁸ they may operate analogously to other DNA-damaging agents (see below). The role of free radicals in mediating myocardial damage in cardiac ischemia and progression of heart failure is now well established. Evidence implicating apoptosis in reperfusion injury^{25 44} and myocardial infarction^{27 42} has recently been reported as noted above, yet definitive proof that antioxidants act by attenuating apoptosis is lacking. However, in an alternative model, maneuvers aimed at attenuating superoxide anion formation in the stretched papillary muscle reduced myocyte apoptosis.¹

TNF-, a pleiotropic cytokine that has been implicated as a contributor to numerous forms of cardiovascular pathology,^{49 50 51 52 53} is a potent inducer of apoptosis in most cell types.⁵⁴ Elevations of this cytokine are observed in patients with heart failure⁵¹ and in infarcted⁵⁰ or reperfused⁴⁹ myocardium. Moreover, TNF- was shown to induce apoptosis in rat cardiac myocytes in vitro.⁵⁵ TNF- is known to signal through two structurally related receptors: the 55-kD type 1 TNFR (TNFR1) and the 75-kD type 2 TNFR (TNFR2). Cardiac myocytes are known to express functionally active receptors of both subtypes.⁵⁶ TNF--induced programmed cell death was associated with increases in sphingosine and could be reproduced with TNFR1-specific ligands, suggesting that cardiac myocyte cell death was secondary to TNFR1-mediated increases in intracellular sphingolipids. Chronic infusion of TNF- in vivo results in the rapid development of a dilated cardiomyopathy, associated with increased myocyte apoptosis (B. Bozkurt and D.L. Mann, unpublished data, 1996). The importance of endogenous TNF- in mediating cardiac myocyte apoptosis in vivo is an intriguing possibility that remains to be tested directly.

It has been noted for some time that abnormal cell cycle events are an important stimulus for apoptosis.^{57 58} In addition to the classic example of cell-cycle progression in the face of DNA damage, forcing cell cycle reentry in terminally differentiated cells also is a potent inducer of programmed cell death.^{59 60 61 62} In efforts to override the cell cycle constraints that preclude regenerative growth via cell proliferation in ventricular muscle, we have used recombinant adenoviruses to deliver the adenoviral protein 12S E1A.⁵⁹ Separable domains of E1A interfere with tumor suppressor "pocket proteins" (the retinoblastoma gene product, Rb, and related proteins) and with the bromodomain transcription factors p300 and CBP. As expected, E1A expression led to DNA synthesis in growth-arrested cardiac myocytes; however, widespread apoptosis occurred in the absence of a second adenoviral protein, E1B,⁵⁹ which is both a structural and a functional homologue of the cellular Bcl-2 proteins discussed immediately below. Since release of E2F transcription factors from their binding site on "pocket proteins" is thought to underlie the action of E1A on the cell cycle, we next sought to determine whether E2F-1 was sufficient for the observed S-phase reentry and induction of apoptosis evoked in cardiac myocytes by the viral protein E1A. Ventricular myocytes thus were infected with a recombinant adenovirus expressing E2F-1.⁶⁰ As shown in the Figure, overexpression of E2F-1 is sufficient to reproduce the effects on cell-cycle reentry and apoptosis seen with E1A, and E2F-1–dependent apoptosis could be rescued with E1B. This finding is particularly germane, since several models of cardiac hypertrophy and failure entail reinduction of DNA synthesis in postmitotic myocytes, accompanied by upregulation of molecular markers for cell-cycle progression.^{29 41 63} Taken together, such findings suggest that reactivation of an E2F-dependent pathway or its equivalent may be one stimulus for cardiac myocyte apoptosis in vivo. (Because the normal biochemical event permitting E2F release is the hyperphosphorylation of pocket proteins and because the available data show no increase in Rb phosphorylation in cardiac muscle subjected to trophic signals in vivo,⁶⁴ the actual mechanism enabling the reinitiation of DNA synthesis, in human heart failure and in the animal models of hypertrophy in which it occurs, remains cryptic.)

View larger version (26K): [in this window] [in a new window]   Figure 1. Schematic representation of the principal classes of proteins that regulate apoptosis in mammalian cells, with the inducers of apoptosis that have been implicated to date in cardiac muscle. ICE/CED-3 proteases are illustrated in yellow; the Fas receptor complex, in blue; the TNF- receptor complex, in green; and Bcl-2 proteins, in red. Oversimplifications in the figure are necessary for the sake of clarity. Interactions that are regarded as particularly speculative are indicated with question marks.

	Molecular Mechanisms of Apoptosis

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
Although little is known of the exact molecular circuit controlling apoptosis in cardiac muscle, it is likely that at least a subset of mechanisms is conserved among cell types. It has been suggested that Bcl-2 family members, including Bcl-2 itself and Bax, may be general mediators of apoptosis. Additional factors involved in apoptotic regulation in cultured mammalian cells include the tumor suppressor p53, ICE/CED-3 family proteases, cytokine receptor Fas/APO-1 and related "death domain" proteins, and the family of mammalian or baculovirus IAPs. Recently, especially strong evidence has been reported for suppression of apoptosis through NF-B. Evidence for a comparable role for these factors in mammalian ventricular myocytes in many cases remains to be established; however, their role in mediating apoptosis more generally will be discussed below.

Bcl-2 Family
Bcl-2 first was identified as a frequent translocation occurring in human B-cell follicular lymphoma and was soon found to function, unlike other oncogenes, by promoting cell survival rather than proliferation. Bcl-2 was initially reported to prevent apoptosis by scavenging oxygen-derived free radicals,⁶⁵ which would have relevance to its putative role in myocardial ischemia and infarction. However, this interpretation now appears to be flawed (eg, Bcl-2 can inhibit cell death even under anaerobic conditions), and other mechanisms of action are at least equally plausible at this time. The Bcl-2 family comprises nearly a dozen mammalian proteins, summarized in the Table, as well as structural or functional homologues, including the adenovirus E1B 19K protein. The adenovirus E1B 19K protein is the best characterized viral homologue for the Bcl-2 family of apoptosis regulators and acts in part by selectively disrupting transcriptional repression by the tumor suppressor protein p53.

View this table: [in this window] [in a new window]   Table 1. Inhibition and Promotion of Apoptosis by Bcl-2 Family Proteins

To date, it has not been possible to address the role of Bcl-2 proteins in myocardial disease using knockout mutations in mice, since Bcl-2–deficient mice die of early postnatal immune failure (loss of T and B cells, resulting from apoptosis) and Bcl-x mice die by embryonic day 13 or 14, with apoptosis of the brain, spinal cord, and hematopoietic organs.¹³ Conversely, targeted expression of Bcl-2 in transgenic mice confers in vivo protection from apoptosis,^{66 67} and a chimeric alphavirus encoding Bcl-2 protects mice from lethal alphavirus encephalitis.⁶⁸

Several of the Bcl-2 homologues were cloned directly on the basis of sequence similarity (Bak and Bcl-W) or physical association with Bcl-2 (Bax and Bad). Three conserved regions, BH1, BH2, and BH3, are present in most Bcl-2 family proteins, with exceptions noted in the Table. Both inhibitors and stimulators of apoptosis exist within the family, suggesting the general model that apoptosis is contingent on the ratio of pro- and anti-apoptotic proteins, perhaps acting as homodimers and heterodimers. The precise mechanism whereby Bcl-2 inhibits and Bax promotes apoptosis is unknown, although much has been made of their colocalization to the mitochondrial membrane. Mutated Bcl-2 molecules lacking the membrane localization domain retain their ability to inhibit apoptosis³⁹ ; however, mutations of domains required for heterodimerization with Bax disrupt its anti-apoptotic activity.⁶⁹ Overexpression studies suggest that Bax-induced apoptosis occurs through ICE protease–dependent and –independent pathways. In addition to the expected activation of ICE-like proteases, Bax expression caused a fall in mitochondrial membrane potential, the production of reactive oxygen species, an increased cytoplasmic vacuolation, and plasma membrane permeability that could not be blocked by ICE protease inhibitors.⁵⁴

p53
p53 is a ubiquitous DNA-binding protein that has been implicated in cell-cycle arrest and in some, but not all, forms of apoptosis. Classically, p53 induces cell-cycle arrest in the G₁ phase through upregulation of p21, a cyclin-dependent kinase inhibitor, in response to DNA damage.⁷⁰ Additionally, p53 induces apoptosis in response to DNA damage⁷¹ and other signals such as E1A⁷² and Myc.⁷³ For this reason, p53 has been proposed as a mechanism for both growth arrest and apoptosis, depending on the cellular context. Bcl-2 family members, including Bcl-2 itself, adenoviral E1B, and Bcl-x_L, inhibit p53-dependent apoptosis. Although several mechanisms for p53-dependent apoptosis have been proposed, differing in part with cell type, two suggestive properties of p53 are its apparent reciprocal effects on Bcl-2 (repression of this "survival" gene) and Bax (activation of this apoptosis gene).^{74 75} Moreover, the ability to induce apoptosis is markedly impaired for p53 mutations that have normal DNA binding but are defective for trans-activation and trans-repression.¹³ Since p53-deficient mice display no observable myocardial defect,⁷⁶ it appears that p53 is dispensable for normal cardiac development; however, this does not preclude a role for this protein in mediating apoptosis in pathological myocardial disorders.

ICE-Related Proteases
Ced-3, a gene required for apoptosis in C elegans, acts downstream from and is antagonized by the Bcl-2 homologue, ced-9, and was found to encode a predicted cysteine protease similar to the mammalian ICE.⁷⁷ Notably, forced expression of ICE or CED-3 is sufficient to trigger apoptosis in mammalian cells, and apoptosis can be blocked, despite their expression, by CrmA (a poxvirus serpine inhibitor of ICE) or by Bcl-2.⁷⁸ Establishing the functional importance of endogenous ICE proteases to apoptosis from diverse causes, CrmA also blocks apoptosis caused by TNF- or by nerve growth factor withdrawal in neurons. The baculovirus inhibitor of apoptosis, p35, is an ICE protease inhibitor, functionally similar to CrmA.⁷⁹

The ICE/CED-3 family (for which the name "caspase" was recently suggested) now includes 10 homologues in humans: CASP-1 (ICE), CASP-2 (ICH-1), CASP-3 (CPP32, Yama, and apopain), CASP-4 (TX, ICH-2, and ICErel-II), CASP-5 (ICErel-III and TY), CASP-6 (Mch2), CASP-7 (Mch3, ICE-LAP3, and CMH-1), CASP-8 (MACH, FLICE, and Mch5), CASP-9 (ICE-LAP6 and Mch6), and CASP-10 (Mch4).⁸⁰ Intriguingly, isolated nuclei can be induced to undergo changes resembling apoptosis in certain cytoplasmic extracts, which are blocked by a specific peptide aldehyde inhibitor of CASP-3, the ICE family member most similar to CED-3.⁸¹ Substrates for cleavage by ICE-like proteases include interleukin-1ß and poly(ADP)ribose polymerase, whose role, if any, in apoptosis may be very indirect, as well as lamins, intermediate filaments of the nuclear envelope, whose cleavage occurs in apoptosis and which, therefore, may be a more physiological target.

One further step in the "molecular ordering" of this ICE/CED-3 pathway was the identification of CASP-8/MACH/FLICE, a protein interacting directly with FADD/MORT1, discussed below. Both CASP-8 and FADD/MORT1 are expressed in adult myocardium, at least at the RNA level.^{82 83} The N-terminal portion of CASP-8 has a consensus death domain, whereas the C-terminal portion corresponds to other ICE/CED-3 proteins. CASP-8 exists as multiple isoforms. Those containing the ICE/CED-3 homology domain are sufficient to cause proteolysis in vitro and apoptosis in transfected cells. As had been shown for ICE itself, apoptosis caused by other family members (CASP-3, -6, and -7) can be blocked by Bcl-2 or by Bcl-x_L, suggesting that Bcl-2 proteins function upstream from the cysteine proteases.^{84 85 86} At least three intermediaries linking Bcl-2 to caspase activation have been proposed, the C. elegans protein CED-4 (or its potential mammalian homologue), mitochondrial release of cytochrome C, and mitochondrial release "apoptosis-inducing factor."⁸⁷ Notably, recent preliminary studies confirm the presence of at least CASP-3 in adult (guinea pig) ventricular myocytes, and staurosporine-induced apoptosis in myocytes is associated with increased CASP-3 expression. A direct role for ICE-like proteases in mediating apoptosis in this and other forms of cardiac cell death is suggested by the ability of z-VAD-fmk, a pharmacological inhibitor of ICE-like proteases,^{88 89} to block this process.

Death Domain Proteins
Two structurally related cytokine receptors, TNFR1 and Fas/APO-1, trigger apoptosis when activated either by their ligands (TNF- and FasL) or by agonist-like antibodies. TNFR2, in contrast, does not. Yeast two-hybrid screens for proteins interacting with these receptors have yielded three that associate with the "death domain" of Fas/APO-1 (FADD/MORT1), TNFR1 (TRADD), or both (RIP). FADD, TRADD, and RIP themselves contain this death domain required for apoptosis, resembling that of the cytokine receptors, which mediate both homotypic and heterotypic protein-protein interactions.

A truncated form of FADD, comprising the C-terminal death domain in the absence of the 79 N-terminal amino acids, also acts as a dominant inhibitor of Fas-induced apoptosis.⁹⁰ As evidence that the dominant-negative effect occurs "upstream" in the apoptotic pathway, the truncated FADD protein (FADD 80-208) also blocked Fas activation of the ICE protease CASP-3 but had no effect on apoptosis elicited by C2-ceramide, a membrane-permeant ceramide analogue.⁹⁰

Novel direct and indirect interactions with the cytoplasmic domain of Fas and TNFR also have been reported. FAF1, a novel Fas-associated protein without homology to death domain or other known proteins, interacts selectively with Fas but not a defective Fas mutation and potentiates Fas-dependent apoptosis.⁹¹ FAP-1, a protein tyrosine phosphatase, binds the C-terminus of Fas and partially inhibits apoptosis.⁹² TRAF2, a TNFR-associated factor, binds TNFR2 directly, recruiting TRAF1 to the receptor; TNFR1 binds both TRAF1 and TRAF2 indirectly, using TRADD as an adaptor protein.⁹³ TRADD also recruits FADD to TNFR1. The dominant-negative FADD protein is a potent inhibitor of apoptosis induced by TNF-, equal in effectiveness to CrmA,^{90 93} lending additional weight to this model.

IAPs and NF-B
One especially intriguing complexity, given this spectrum of potential effector proteins, is that TNF- both promotes apoptosis (via FADD) and suppresses apoptosis (via TRAF2 and RIP, which lead to activation of NF-kB).⁹⁴ NF-kB itself now is known to be a potent suppressor of apoptosis in vitro and in vivo, although few triggers other than TNF- have been tested thus far.^{95 96 97} This protective effect of TNF- also has been linked to mammalian homologues of a baculovirus IAP.^{98 99 100} Certain of these are bound to TRAF2 and TRAF1 and are postulated to draw TRADD away from FADD, lessening activation of the ICE/CED-3 pathway, but they increase signaling through NF-B.¹⁰¹ Several mammalian IAPs block apoptosis triggered by ICE, serum withdrawal, or free radicals, with some differences contingent on cell type.^{99 100} Another, NAIP, is mutated in patients with spinal muscular atrophy, a neurodegenerative disease; NAIP already has been proven to protect a variety of cells from apoptosis caused by TNF-, serum deprivation, and free radicals, when delivered by transfection or adenoviral gene transfer.⁹⁹ This wide range of actions and the array of cells in which protection already has been shown favor the prediction that NAIP will have relatively general effects as an apoptosis inhibitor.

	Future Directions

Top Abstract Introduction Apoptosis in Normal Cardiac... Apoptosis Occurs With... Inducers of Apoptosis in... Molecular Mechanisms of... Future Directions References

 
Recent advances in elucidating the general mechanisms of programmed cell death have heightened investigators' awareness of the role of apoptosis in cardiac development and disease. Apoptosis is now recognized as a principal cause of cardiac muscle death in ischemia/reperfusion injury or the early hours of infarction and as a possible contributor to congestive heart failure. Notwithstanding intensive efforts aimed at myocardial "salvage" by other approaches, no current therapeutic strategies are targeted at establishing feasibility for the rescue of cardiac muscle from cell death by apoptosis. In this regard, preliminary studies with growth factors, such as insulin-like growth factor-I⁴⁴ and cardiotrophin-1,¹⁰² to promote cardiac myocyte survival are encouraging. Mechanistic studies of apoptosis in cardiac muscle are lacking, despite their fundamental and applied importance. The rapid development of cardiac models in which apoptosis is operative, as well as the identification of new inhibitors that has occurred in recent years, should allow direct manipulation of the apoptotic pathways in cardiac muscle to explore this strategy. Understanding the mechanisms that mediate apoptosis in cardiac muscle and the genes that prevent it is the indispensable prerequisite for more applied studies aimed at averting apoptosis in vivo.

	Selected Abbreviations and Acronyms

 

CASP, caspase = cysteine proteases cleaving after aspartic acid FADD/MORT = Fas-associated "death domain" protein FLICE = FADD-like ICE IAP = inhibitor of apoptosis protein ICE = interleukin-1ß–converting enzyme MACH = MORT1/FADD-associated CED-3 homologue NAIP = neuronal apoptosis inhibitor protein NF = nuclear factor RIP = receptor-interacting protein TNF = tumor necrosis factor TNFR = TNF receptor TRADD = TNFR1-associated "death domain" protein TRAF = TNFR-associated factor

	Acknowledgments

 
This study was supported in part by grants to Dr Schneider from the National Institutes of Health (RO1 HL-47567, RO1 HL-52555, PO1 HL-49953, and P50 HL-42267). Dr MacLellan is a recipient of the Pfizer Scholars Award for New Faculty. We are grateful to John Cooke, Pavel Hamet, Doug Mann, David Spencer, Ralph Shohet, and Ed Yeh for sharing preliminary results and helpful discussions.

Received March 3, 1997; accepted May 8, 1997.

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