TY - JOUR
AU - Snyder, Solomon H.
AB - Programmed cell death, also called apoptosis, participates not only in normal physiologic processes such as development of the immune system, but also in many diseases. A loss of normal cell death may occur in cancer, and excessive cell death is found in a variety of neurodegenerative conditions. We describe 3 distinct pathways that regulate cell death. First, bilirubin, often thought to be a toxic end product of heme metabolism, serves as a physiologic cytoprotectant that may attenuate multiple forms of morbidity. In a second pathway, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mediates a novel cell death cascade. Cytotoxic stimuli, via nitric oxide generation, lead to the binding of GAPDH to the protein Siah1, translocation of GAPDH-Siah1 to the nucleus, and ultimately cell death. Third, cytochrome c, released from mitochondria early in apoptosis, synergizes with inositol-1,4,5-triphosphate (IP3) to elicit massive cellular calcium release, resulting in cell death. These pathways may regulate cell survival in a variety of pathologic states and represent fertile targets for novel therapies.Nobel Laureate Julius (“Julie”) Axelrod often commented, “Nature is very efficient. If she finds a good molecule, she uses it over and over again.” He was likely thinking of molecules such as histamine, which, besides its role in allergic reactions, possesses distinct roles as a mediator of gastric acid secretion and as a neurotransmitter in the brain. Sometimes, diverse roles of messenger molecules reflect coordinated functions. Thus, angiotensin II stimulates sodium retention through adrenal formation of aldosterone, enhances blood vessel contraction, and, in the brain, augments drinking behavior. More instances are appearing that neurotransmitter-related systems play major roles in biology beyond neurotransmission. A similar diversity of function is evident for nonneural messenger systems. In many cases, these actions influence cell death and suggest novel approaches to therapy in diverse conditions such as stroke, myocardial infarction, and neurodegenerative disease.In this account, drawn in large part from work conducted in our own laboratory, we review 3 novel signaling pathways that reflect novel ways in which cells are protected from potentially lethal insults and also review new cascades involved in programmed cell death, also known as apoptosis.Necrosis and Apoptosis: Distinct Ways for Cells to DieJust as there are any number of means by which a person might meet his or her demise, individual cells can die by a variety of processes. Two of the best-described types of cell death are known as necrosis and apoptosis.In necrosis, the process perhaps best known to clinicians, cells are exposed to a pathophysiologic stress—eg, myocardial ischemia, hypoglycemia, infection, or inflammation—leading to a florid swelling and rupture of the cell. As the mitochondria—the principal source of energy in the cell—disintegrate, cellular energy levels are depleted, leading to disintegration of various other organelles. To use a legal metaphor, necrosis is murderof the cell, which is an unwilling participant.By contrast, apoptosis is cellular suicide—ie, the cell is an active participant in its own death. For instance, death receptors (eg, Fas) on the cell surface activate a cascade of executioner enzymes known as caspases, leading to an irreversible commitment to cellular death.Morphologically, necrosis differs from apoptosis. Whereas necrosis is characterized by cellular rupture, in apoptosis the cell membrane becomes permeable to the outside environment yet remains relatively contiguous; cellular chromatin condenses and is cleaved into small fragments as the nucleus disintegrates. Although energy depletion can result in necrosis, energy is required for apoptosis. Whereas necrosis also generally produces an inflammatory response, apoptosis does not.Although necrosis is typically pathologic, apoptosis may be either physiologic or pathologic. For instance, excess numbers of neurons in the developing brain are eliminated by normal apoptotic death. If this process is disrupted, brain dysfunction and malformation may occur.Normal apoptosis is also required to avoid webbing between the digits of the extremities and to remove autoreactive or improperly developed T and B cells of the immune system.Inefficient or dysregulated apoptosis may lead to cancer, and necrosis and apoptosis both occur in neurodegenerative conditions such as amyotrophic lateral sclerosis, as well as Alzheimer, Huntington, and Parkinson diseases.Three Pathways Regulating Cell DeathCytoprotection by the Bilirubin Pathway. Neurotransmitters come in chemical classes. The biogenic amines—acetylcholine, norepinephrine, serotonin, and others—were the first neurotransmitters to be identified, followed by amino acids such as γ-aminobutyric acid, glutamate, and glycine. Peptides such as the opioid peptides, the enkephalins and endorphins, and substance P were subsequently identified. Gaseous transmitters are the most recent class, with nitric oxide functioning both in the brain and peripheral autonomic nervous system in addition to its roles as a determinant of blood vessel relaxation and regulator of macrophage function.More recently, carbon monoxide has been shown to be a neurotransmitter formed by heme oxygenase (HO), which exists in 2 forms, HO-1 and HO-2. First discovered was HO-1, which is concentrated in the spleen, where it degrades heme released from aging red blood cells. Heme oxygenase breaks open the heme ring, releasing iron and carbon monoxide and giving rise to the green pigment biliverdin, which is rapidly reduced by biliverdin reductase (BVR) to the yellow pigment bilirubin (Figure 1). In the liver, conjugation enzymes attach sugar residues to bilirubin to make it more water soluble, allowing its passage into bile. Aside from its neurotransmitter properties, carbon monoxide has also been shown to activate a variety of intracellular signaling pathways.Its antiproliferative properties at low doses may offer promise in treating atherosclerotic disease.Figure 1.Pathway of Bilirubin Production and Recycling by Biliverdin Reductase and Production of Carbon MonoxideBilirubin is generated by the sequential action of 2 enzymes, heme oxygenase and biliverdin reductase. In the first reaction, the heme ring is broken open and leads to the production of biliverdin, iron, and the gaseous messenger molecule, carbon monoxide (CO). Cytochrome P450 reductase provides reducing equivalents for the reaction. In the second reaction, biliverdin is reduced to the yellow pigment bilirubin, which itself may serve as an antioxidant and revert back to biliverdin. The recycling function of biliverdin reductase explains the ability of bilirubin to detoxify a 10 000-fold excess of oxidants. Inhibition of bilirubin conjugation may be a useful target to mildly increase bilirubin levels for clinical benefit. NADP indicates nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP.HO-1 is an inducible enzyme whose synthesis is rapidly and profoundly augmented by myriad cell stressors, including most inflammatory stimuli as well as heat shock. Hence, it is also known as heat shock protein 32. Heme itself is one of the most powerful inducers of HO-1.Evidence for a role of the HO system in cellular protection came from studies of HO-2gene knockout mice,the enzyme form predominantly found in the brain and testes. These mice are much more sensitive to stroke damage than are normal mice. Moreover, brain cultures of these knockout mice display far greater degrees of cell death in response to oxidant stressors such as hydrogen peroxide than do control cultures.Loss of formation of biliverdin and bilirubin explains the augmented neurotoxicity.Remarkably, bilirubin acting as an antioxidant combats the oxidative stress elicited by 10 000-fold higher concentrations of hydrogen peroxide, which at first seems impossible.The resolution to this dilemma came with the identification of a novel BVR cyclethat regenerates bilirubin (Figure 1). Thus, bilirubin acting as an antioxidant can itself be oxidized to its precursor, biliverdin. Tissue levels of biliverdin do not accumulate, because biliverdin is rapidly reduced to bilirubin through the action of biliverdin reductase, an enzyme abundantly expressed in many tissues. Therefore, as soon as a molecule of bilirubin is oxidized to biliverdin, it is immediately recycled to bilirubin.Assuming that bilirubin is a physiologic cytoprotectant, this regenerative cycle makes good sense. Very high levels of bilirubin can have toxic effects such as kernicterus, the deposition of bilirubin in the basal ganglia of the brain. Recycling of bilirubin by the BVR cycle allows the cell to keep bilirubin levels low enough to be safe but still effective as an antioxidant. Evidence that this BVR cycle is a physiologic cytoprotectant comes from experiments in which BVR was depleted from tissues by RNA interference technology. In these tissues, reactive oxygen species accumulated to very high levels, and the cells became much more sensitive to cell stressors.Reactive oxygen species are generally regarded as a final common pathway for cell death and are elicited by all manner of tissue insults, such as ischemia associated with myocardial infarction or stroke, inflammatory stimuli such as endotoxin, and many anticancer drugs. Reactive oxygen species are also generated in the mitochondria as part of the multiple metabolic processes of normal physiology. In susceptible cells, low levels of oxidants can lead to apoptosis, but high levels can cause necrotic death.To protect cells from physiologic and pathologic oxidative stress, cells require endogenous, physiologic cytoprotectants. The tripeptide glutathione (γ-glutamyl-cysteinyl-glycine), which occurs in all tissues in high millimolar levels, has generally been accepted as the major cytoprotectant for most tissues. Depleting tissue glutathione levels by 95% through treatment with buthionine sulfoximine, which inhibits the glutathione-synthesizing enzyme γ-glutamylcysteine synthase, increases levels of reactive oxygen species and augments cell death but to a lesser extent than does depletion of bilirubin.It appears likely that both bilirubin and glutathione are physiologic cytoprotectants. By detoxifying oxidants, they can block both necrotic and apoptotic types of cell death. They also serve complementary functions. Thus, the lipophilic bilirubin may protect cells against damage to cell membranes caused by lipid peroxidation, while the hydrophilic glutathione may protect water-soluble proteins.Evidence for this comes from experiments in which depletion of BVR leads to a relatively selective augmentation of lipid peroxidation, while depletion of glutathione selectively augments oxidative damage to water-soluble proteins.Bilirubin and glutathione are clearly not the only endogenous cytoprotectant systems. Enzymes such as superoxide dismutase and catalase, which act in concert, convert superoxide to water. Also, the vitamins ascorbate (vitamin C) and α-tocopherol (vitamin E) exert antioxidant actions, as does uric acid.Mildly Elevated Bilirubin Levels: Clinical Implications. There are clinical ramifications of bilirubin's physiologic cytoprotectant role.Several studies suggest that mildly to moderately elevated levels of serum bilirubin offer therapeutic advantage in diseases associated with oxidative stress. Multiple investigators have linked elevated serum bilirubin levels with diminished risk of coronary artery disease. In studies using data from the Framingham cohort, higher bilirubin levels were associated with a lower risk of myocardial infarction and other cardiovascular events.In one case-control study, patients with a familial history of coronary artery disease demonstrated lower serum bilirubin levels than did those without such a history.The protective effect of bilirubin in this study was comparable with that afforded by high-density lipoprotein cholesterol.Gilbert syndrome is a common genetic disorder presenting as mild to moderate augmentation of unconjugated bilirubin caused by impairment of bilirubin conjugation.In one study, the prevalence of ischemic heart disease in individuals with Gilbert syndrome was 2%, or one sixth that of the control population, and elevated bilirubin level was more prominent as a protective index than was high-density lipoprotein cholesterol.A meta-analysis of 11 studies revealed a diminished risk of atherosclerosis in individuals with elevated bilirubin levels.In a large patient population screened for carotid stenosis, elevated bilirubin levels were associated with a 32% reduction in the risk of carotid plaques.While very high levels of serum bilirubin in infants are unquestionably toxic, some investigators have reported a decreased incidence of the retinopathy of prematurity in infants with elevated serum bilirubin levels,though others have not observed such a relationship.Neonatal Gunn rats, whose elevated levels of serum unconjugated bilirubin result from a genetic defect causing a lack of glucuronidation, resist oxidative damage when they are exposed to high oxygen levels.These findings may have direct therapeutic implications. In rodents, induction of HO-1 by treatment with porphyrin derivatives protects against ischemic insults.Intravenous administration of bilirubin diminishes drug-elicited pulmonary fibrosisand intestinal ischemic-reperfusion injuryin animal models. Moreover, rinsing liver grafts with bilirubin leads to diminished postgraft injury.Although bilirubin may become toxic when its concentrations increase to levels 15 to 50 times normal, this is actually a much safer toxicity profile than that of sodium, potassium, calcium, or cortisol, in which morbidity results from doubling or tripling of serum levels. Although most studies measure levels of serum bilirubin, it may actually be tissue bilirubin—which is more difficult to assess—that mediates beneficial effects.A single case of human HO-1 deficiency has been reported, occurring in an individual who inherited a defective allele from each parent.The patient displayed hemolytic anemia, asplenia, cellular sensitivity to oxidative damage, damaged vascular endothelia, renal tubular injury, and coagulopathy before succumbing to intracranial hemorrhage at age 6 years. The human HO-1gene has at least 3 different genetic polymorphisms associated with a reduced ability to increase its expression following oxidative stress.These polymorphisms have been associated with emphysema in smokers, renal allograft deterioration, idiopathic miscarriage, coronary artery disease, and restenosis following angioplasty or stenting.Genetic studies have suggested that uridine diphosphate glycosyltransferase 1 contributes to mildly elevated bilirubin levels, which in turn protect against coronary artery disease.This enzyme conjugates bilirubin with sugar residues so that it may be excreted in bile. Inhibitors of bilirubin conjugation and excretion represent a means by which bilirubin levels could be mildly increased for beneficial effects.Glyceraldehyde-3-Phosphate Dehydrogenase and a Novel Cell Death Cascade. The concept of multiple, diverse functions for proteins and small molecules has recently been extended to common “housekeeping” glycolytic enzymes. For instance, in iron-depleted cells, cytosolic aconitase loses its catalytic activity and is transformed into the protein called iron regulatory protein, which can bind specific RNA hairpin loop structures called iron-responsive elements. Activation of IRPs augments expression of the transferrin receptor, thus facilitating iron entry into cells, but decreases expression of the iron storage protein ferritin.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also displays nonglycolytic functions. During apoptotic cell death, GAPDH translocates to the nucleus.Antisense oligonucleotides that deplete GAPDH prevent this nuclear translocation and reduce cell death.These events appear to reflect a novel signaling pathway involving nitric oxide as an initial trigger to cell death (Figure 2).Figure 2.Cell Death Pathway of Nitric Oxide (NO), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), and Siah1Nitric oxide, a gaseous messenger released in response to cell death stimuli, is produced by the action of nitric oxide synthase (NOS), which uses the amino acid arginine as a substrate. Nitric oxide nitrosylates GAPDH at sulfur residues, and the S-nitrosylated GAPDH binds to and stabilizes the cell death protein Siah1, after which the GAPDH-Siah1 complex enters the nucleus and promotes cell death. Molecules that disrupt the GAPDH-Siah1 interaction, such as deprenyl and TCH346, may prove useful in blocking cell death. NADP indicates nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP.Nitric oxide is derived from the amino acid arginine following catalytic activity of nitric oxide synthase (NOS), which abstracts nitric oxide from the guanidino group of arginine, giving rise to citrulline as a by-product (Figure 2). There are 3 distinct forms of NOS derived from 3 different genes.Neuronal NOS is the predominant form in the brain.It is not inducible but instead is rapidly activated by calcium via the accessory protein calmodulin.In this way, generation of nitric oxide can take place following neuronal depolarization, which is associated with rapid calcium influx.Endothelial NOS occurs predominantly in blood vessels and, like neuronal NOS, is a constitutive enzyme that is stimulated by calcium-calmodulin, affording rapid, transient activation.More prolonged activation of endothelial NOS occurs in response to shear stress associated with turbulent blood flow, which, via the phosphoinositide 3 kinase cascade, leads to phosphorylation and long-term activation of endothelial NOS by the enzyme Akt (protein kinase B).Inducible NOS (iNOS) exists at very low tissue levels under basal conditions, but massive new synthesis of iNOS occurs in response to almost any form of cell stress, especially inflammatory stimuli.In this way, the behavior of iNOS closely resembles that of HO-1.Nitric oxide signals via 2 principal systems. In one mode, nitric oxide activates guanylyl cyclase to form guanosine 3′,5′-cyclic monophosphate, which accounts for its ability to relax smooth muscle and dilate blood vessels. A more recently appreciated signaling mode for nitric oxide is called S-nitrosylation, whereby nitric oxide covalently modifies cysteine in target proteins by forming a S-nitrosothiol group.This process is reversible spontaneously or by selective denitrosylation enzymes.Targets for S-nitrosylation include a wide range of proteins, such as the sodium pump, sodium-potassium ATPase, the microtubule protein alpha-tubulin, the N-methyl-D-aspartate subtype of receptor for actions of the excitatory neurotransmitter glutamate, and GAPDH.Evidence for physiologic S-nitrosylation comes from experiments showing that these proteins are no longer S-nitrosylated in the brains of mice with targeted deletion of nNOS.Recent studies indicate that a wide range of apoptotic cell stressors acting on many different cell types consistently induce iNOS and lead to S-nitrosylation of GAPDH, triggering its nuclear translocation.Proteins such as GAPDH, which move from the cytoplasm to the nucleus of cells, typically contain a “nuclear localization signal” that enables the importin system of the nuclear membrane to grant them entry. However, GAPDH lacks a nuclear localization signal, which raises the question of how it gets into the nucleus. Recent studies show that S-nitrosylation of GAPDH confers on it the ability to bind to a protein called Siah1, which possesses a nuclear localization signal.Siah1 is an E3-ubiquitin-ligase, a member of a class of enzymes that mediate the ubiquitin-associated degradation of proteins in the proteasome, and is well known to elicit cell death by causing the degradation of selected nuclear proteins.When S-nitrosylated GAPDH binds to Siah1, the 2 proteins enter the nucleus. Normally Siah1 turns over very rapidly, but after binding to GAPDH its turnover is slowed down, enabling it to more efficiently degrade its nuclear substrates, thus leading to cell death.Evidence for the GAPDH-Siah1 apoptotic cascade includes experiments in which selected mutations that prevent GAPDH from binding to Siah1 prevent nuclear translocation of GAPDH.Similarly, inhibition of iNOS and depletion of GAPDH or Siah1 from cells by RNA interference techniques prevent cell death.The iNOS-GAPDH-Siah1 cell death cascade provides a unique pathway extending from the external surface membrane of cells to the nucleus. Diverse cell stressors all have in common the ability to induce iNOS, leading to the formation of nitric oxide, which S-nitrosylates GAPDH. S-nitrosylated GAPDH binds to Siah1, which escorts it to the nucleus. In the nucleus, GAPDH stabilizes the rapidly turning over Siah1, enabling it to use its E3-ubiquitin-ligase activity to degrade nuclear target proteins and bring about apoptotic cell death.iNOS-GAPDH-Siah1: Clinical Implications. Though only recently identified, the iNOS-GAPDH-Siah1 pathway already has demonstrated clinical ramifications. Huntington disease is caused by a dominant genetic abnormality leading to the formation of a mutant form of the protein huntingtin.Huntington disease is associated with an expansion of repeats of the nucleotide triplet CAG, which codes for glutamine so that mutant huntingtin (mHtt) possesses 30 to 200 glutamine repeats.Abundant evidence indicates that neuronal damage in Huntington disease derives from the translocation to the nucleus of the N-terminal fragment of mHtt.We recently showed that this translocation is mediated via the binding of mHtt to GAPDH.Molecular manipulations that prevent this binding in neuronal cell lines prevent nuclear translocation of mHtt and prevent neurotoxicity. A genetic association study recently found an association between GAPDH and late-onset Alzheimer disease, suggesting that GAPDH variants may predispose to dementia.These findings have clear therapeutic implications. For example, drugs that block the binding of GAPDH to Siah1 would be anticipated to prevent cell death. Interestingly, such drugs already appear to exist. The monoamine oxidase inhibitor deprenyl has been used in the treatment of Parkinson disease for many years.It had been assumed that deprenyl acts by simply increasing brain levels of dopamine, hence correcting the dopamine deficiency of the disease in a fashion analogous to that exerted by levodopa. However, in animal studies deprenyl has been found to be neuroprotective, protecting against the loss of dopamine neurons elicited via various dopamine neuronal toxins.Human studies have also suggested that deprenyl has neuroprotective effects, though some controversy exists as to whether the benefit is symptomatic or neuroprotective.To aid in distinguishing the inhibitory effect of monoamine oxidase from the neuroprotective effects of deprenyl, very potent derivatives have been synthesized that do not inhibit monoamine oxidase. One of these, TCH346 (CGP3466), exerts neuroprotective effects even at concentrations as low as 1 nanomolar.TCH346 binds to a single brain protein, identified as GAPDH,and deprenyl and TCH346 both prevent the binding of GAPDH to Siah1.The therapeutic applicability of drugs such as deprenyl and TCH346 may extend well beyond Parkinson disease and may be relevant to many nonneurologic as well as neurologic conditions in which cell death is a mediator of clinical pathologic processes.Cytochrome c and Calcium Release in Apoptotic Cell Death. Inositol-1,4,5-trisphosphate (IP3) is one of the 2 principal second messengers of biology, the other being cyclic adenosine monophosphate (AMP). When neurotransmitters or hormones act on cell-surface membrane receptors, they activate phospholipase C, which cleaves lipid membranes to generate IP3, which in turn then acts on specific receptors located on the endoplasmic reticulum, leading to the release of intracellular calcium.In addition to its role in physiological intracellular signaling, calcium release elicited by IP3 can also lead to apoptotic cell death. Release of intracellular calcium causing apoptosis can arise from a variety of sources in addition to IP3 receptors, as damage to cell membranes and opening of cell membrane calcium channels may also be involved.In some types of cell death, mitochondria become overloaded with calcium, activating a mitochondrial opening referred to as the permeability transition pore. This opening is associated with permeabilization of the mitochondria, leading to the release of a variety of proteins that activate cell death.Most prominent among these is cytochrome c, a small, heme-containing protein of the electron transport chain. Cytochrome c binds to a protein called apoptotic protease activating factor 1 (APAF-1), which recruits one of the caspase enzymes, caspase-9, to initiate a sequence of cleavage and activation of other caspases that ultimately results in cell death.Recent studies indicate an intimate link between cytochrome c and IP3-elicited release of calcium, reflecting a novel cell death pathwaythat might be approached therapeutically (Figure 3). Thus, when cytochrome c is released from mitochondria in the initial stages of apoptosis, it passes to the closely adjacent membrane of the endoplasmic reticulum and physiologically binds IP3 receptors there. Extremely low concentrations of cytochrome c block a feedback system in which released calcium normally inhibits the ability of IP3 to provoke further calcium release. Blocking this feedback system leads to unrestrained release of calcium. This calcium enters mitochondria to provoke further release of cytochrome c. This feed-forward system spreads throughout the cell, leading to cell-wide coordinated release of cytochrome c.Figure 3.Cytochrome c, Inositol-1,4,5-Triphosphate (IP3) Receptors, and Calcium Release During Cell DeathCytochrome c–IP3 Receptor: Clinical Implications. The cytochrome c–IP3 binding system may provide novel therapeutic strategies. It has been possible to map the exact amino acids in the IP3 receptor responsible for binding to cytochrome c. A cell-permeable peptide derived from this sequence prevents the binding of cytochrome c to IP3 receptors and prevents cell death in various cell lines.This peptide could represent a novel therapeutic approach to preventing cell death, but clinicians may also readily screen for small-molecule drugs to block the binding of cytochrome c to the IP3 receptor. Such drugs might be beneficial in preventing cell death in conditions such as stroke, in which excessive cellular calcium is associated with cell death. The IP3 receptor was also recently shown to interact with the antiapoptotic protein, Bcl-2, underlining its role in regulating cell death.NecrosisMechanisms and Potential Drug Targets. In some conditions, eg, neurodegenerative conditions such as Alzheimer, Huntington, and Parkinson diseases, the relative roles of necrosis and apoptosis are controversial. Apoptosis is currently better understood, and several molecular pathways have been characterized, consistent with a need for redundancy in such a critical aspect of cellular disposition.Less molecular characterization has been achieved for necrotic death. One necrotic pathway involves activation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP),a nuclear enzyme that adds poly(ADP-ribose) groups both to itself and to nuclear proteins such as histones. Nicotinamide adenine dinucleotide (NAD) is the donor of the ADP-ribose groups for this process. The massive activation of PARP that occurs during necrosis leads to a depletion of NAD and, secondarily, to a depletion of adenosine triphosphate (ATP) so that cells die of energy deficit.Targeted deletion of PARP-1, the major nuclear form of this enzyme, greatly reduces stroke infarct size,pancreatic islet cell damage in models of diabetes,and damage from myocardial infarction.Necrotic Death and PARP: Clinical Implications. There are more than 2 dozen PARP inhibitor drugs, several of which have shown efficacy in animal models for treating stroke, Parkinson disease, myocardial infarction, ischemic colitis, and other conditions.Two of these compounds, INO-1001 and AG140699, are currently being tested in human phase 1 or phase 2 trials for a number of applications, including treatment of myocardial infarction and prevention of complications associated with surgical repair of abdominal aortic aneurisms. Although there are likely multiple undiscovered molecular mechanisms by which cells may die of necrosis, PARP inhibitor drugs are attractive candidates for attenuating cell injury in stroke, myocardial infarction, and other disease states.ConclusionsTherapeutic agents acting via cell death and cell protective pathways are likely to become increasingly prominent in the next few decades. Prevention of cell death will be of importance in stroke, myocardial infarction, and neurodegenerative conditions, while highly selective augmentation of cell death will be sought in anticancer drugs.Apoptosis is a normal physiologic event in organs such as the developing thymus, brain, and bone marrow. Antiapoptotic drugs might disrupt this normal cell death, and their use may have to be avoided during critical periods of development or limited to acute phases of disease pathogenesis. Neurodegenerative diseases might require chronic treatment with antiapoptotic drugs, necessitating careful monitoring of adverse effects. Drugs that promote apoptosis may have the adverse effect of killing healthy cells, requiring exquisite dosing and follow-up as is done with cancer chemotherapeutic agents that are similarly toxic to healthy cells.The cytoprotective actions of bilirubin derive from its antioxidant properties and would presumably be relevant to both necrotic and apoptotic instances of cell death. Drugs that prevent cytochrome c–IP3 receptor binding and the iNOS-GAPDH-Siah1 cascades would presumably be relevant only for apoptotic cell death, the only form for which these 2 pathways have been implicated.Corresponding Author:Solomon H. Snyder, MD, Department of Neuroscience, Johns Hopkins School of Medicine, Wood Basic Sciences Bldg 813, 725 N Wolfe St, Baltimore, MD 21205 (ssnyder@bs.jhmi.edu).Financial Disclosures:None reported.Funding/Support:This work was supported by United States Public Health Service grant DA-00266, Center grant MH68830, and Research Scientist Award DA-00074 (Dr Snyder), and Pfizer Postdoctoral Fellowships (Dr Sedlak).Role of the Sponsors:The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.Acknowledgment:We thank Darren Boehning, PhD, University of Texas, Galveston, and Makoto Hara, PhD, Daniel Higginson, Krishna Juluri, and Graham Redgrave, MD, Johns Hopkins School of Medicine, for their helpful comments.REFERENCESPSyntichakiNTavernarakisThe biochemistry of neuronal necrosis: rogue biology?Nat Rev Neurosci2003467268412894242HOkadaTWMakPathways of apoptotic and non-apoptotic death in tumour cells.Nat Rev Cancer2004459260315286739NNDanialSJKorsmeyerCell death: critical control points.Cell200411620521914744432RHakemAHakemGSDuncanDifferential requirement for caspase 9 in apoptotic pathways in vivo.Cell1998943393529708736KKuidaTFHaydarC-YKuanReduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.Cell1998943253379708735HYoshidaY-YKongRYoshidaApaf1 is required for mitochondrial pathways of apoptosis and brain development.Cell1998947397509753321FCecconiGAlvarez-BoladoBIMeyerKARothPGrussApaf1 (CED-4 homolog) regulates programmed cell death in mammalian development.Cell1998947277379753320FRieux-LaucatAFischerFLDeistCell-death signaling and human disease.Curr Opin Immunol20031532533112787759SWRyterDMorseAMKChoiCarbon monoxide: to boldly go where NO has gone before.Sci STKE2004230RE615114002LEOtterbeinBSZuckerbraunMHagaCarbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury.Nat Med2003918319012539038HPKimXWangANakaoCaveolin-1 expression by means of p38β mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide.Proc Natl Acad Sci U S A2005102113191132416051704SDoreKSampeiSGotoHeme oxygenase-2 is neuroprotective in cerebral ischemia.Mol Med1999565666310602774SDoreSGotoKSampeiHeme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia.Neuroscience20009958759210974422EFChangRJWongHJVremanHeme oxygenase-2 protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury.J Neurosci2003233689369612736340SDoreMTakahashiCDFerrisBilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.Proc Natl Acad Sci U S A1999962445245010051662DEBarananoMRaoCDFerrisSHSnyderBiliverdin reductase: a major physiologic cytoprotectant.Proc Natl Acad Sci U S A200299160931609812456881TWSedlakRGCutlerMPMattsonSHSnyderProtective effects of bilirubin in accumulation of oxidant-associated lipid changes.Presented at: Society for Neuroscience 34th Annual Meeting; October 23-27, 2004; San Diego, CalifBHalliwellJMCGutteridgeFree Radicals in Biology and Medicine.3rd ed. Oxford, England: Oxford University Press; 1999TWSedlakSHSnyderBilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle.Pediatrics20041131776178215173506LVitekImpact of serum bilirubin on human diseases.Pediatrics20051151411141215867053LDjousseDLevyLACupplesJCEvansRBD’AgostinoRCEllisonTotal serum bilirubin and risk of cardiovascular disease in the Framingham Offspring Study.Am J Cardiol20018711961200, A4, A711356398LDjousseKJRothmanLACupplesDLevyRCEllisonEffect of serum albumin and bilirubin on the risk of myocardial infarction (the Framingham Offspring Study).Am J Cardiol20039148548812586275PNHopkinsLLWuSCHuntBCJamesGMVincentRRWilliamsHigher serum bilirubin is associated with decreased risk for early familial coronary artery disease.Arterioscler Thromb Vasc Biol1996162502558620339MKaplanCHammermanMJMaiselsBilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation.Pediatrics200311188689312671128LVitekMJirsaMBrodanovaGilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels.Atherosclerosis200216044945611849670LNovotnyLVitekInverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies.Exp Biol Med (Maywood)200322856857112709588NIshizakaYIshizakaETakahashiMYamakadoHHashimotoHigh serum bilirubin level is inversely associated with the presence of carotid plaque.Stroke20013258058311157203EHeymanAOhlssonPGirschekRetinopathy of prematurity and bilirubin.N Engl J Med19893202562911316KLYeoMPerlmanYHaoPMullaneyOutcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy.Pediatrics1998102142614319832580BRBoyntonCABoyntonRetinopathy of prematurity and bilirubin.N Engl J Med19893211931942747756DDGatonJGoldRAxer-SiegelEWielunskyNNaorINissenkornEvaluation of bilirubin as possible protective factor in the prevention of retinopathy of prematurity.Br J Ophthalmol1991755325341911654JCFauchereFEMeier-GibbonsFKoernerEBossiRetinopathy of prematurity and bilirubin—no clinical evidence for a beneficial role of bilirubin as a physiological anti-oxidant.Eur J Pediatr19941533583628033927SHosonoTOhnoHKimotoNo clinical correlation between bilirubin levels and severity of retinopathy of prematurity.J Pediatr Ophthalmol Strabismus20023915115612051280MHDeJongeAKhuntiaMJMaiselsABandagiBilirubin levels and severe retinopathy of prematurity in infants with estimated gestational ages of 23 to 26 weeks.J Pediatr199913510210410393613JDMilnerHZAlyLBWardAEl-MohandesDoes elevated peak bilirubin protect from retinopathy of prematurity in very low birthweight infants.J Perinatol20032320821112732858PADenneryAFMcDonaghDRSpitzPARodgersDKStevensonHyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia.Free Radic Biol Med1995193954047590389FAmersiRBuelowHKatoUpregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury.J Clin Invest19991041631163910587527HDWangMYamayaSOkinagaBilirubin ameliorates bleomycin-induced pulmonary fibrosis in rats.Am J Respir Crit Care Med200216540641111818329CHammermanDGoldschmidtMSCaplanProtective effect of bilirubin in ischemia-reperfusion injury in the rat intestine.J Pediatr Gastroenterol Nutr20023534434912352525YKatoMShimazuMKondoBilirubin rinse: a simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning.Hepatology20033836437312883480AYachieYNiidaTWadaOxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.J Clin Invest19991031291359884342KOhtaAYachieKFujimotoTubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency.Am J Kidney Dis20003586387010793020AKawashimaYOdaAYachieSKoizumiINakanishiHeme oxygenase-1 deficiency: the first autopsy case.Hum Pathol20023312513011823983MExnerEMinarOWagnerMSchillingerThe role of heme oxygenase-1 promoter polymorphisms in human disease.Free Radic Biol Med2004371097110415451051TGulesserianCWenzelGEndlerClinical restenosis after coronary stent implantation is associated with the heme oxygenase-1 gene promoter polymorphism and the heme oxygenase-1 +99G/C variant.Clin Chem2005511661166516020495FKronenbergHCoonAGutinA genome scan for loci influencing anti-atherogenic serum bilirubin levels.Eur J Hum Genet20021053954612173031RSEisensteinIron regulatory proteins and the molecular control of mammalian iron metabolism.Annu Rev Nutr20002062766210940348GCairoSRecalcatiAPietrangeloGMinottiThe iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage.Free Radic Biol Med2002321237124312057761ASawaAAKhanLDHesterSHSnyderGlyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death.Proc Natl Acad Sci U S A19979411669116749326668RIshitaniMTanakaKSunagaNKatsubeD-MChuangNuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis.Mol Pharmacol1998537017079547361RIshitaniD-MChuangGlyceraldehyde-3-phosphate dehydrogenase antisense oligodeoxynucleotides protect against cytosine arabinonucleoside-induced apoptosis in cultured cerebellar neurons.Proc Natl Acad Sci U S A199693993799418790435MRHaraNAgrawalSFKimS-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.Nat Cell Biol2005766567415951807WKAldertonCECooperRGKnowlesNitric oxide synthases: structure, function and inhibition.Biochem J200135759361511463332DSBredtPMHwangSHSnyderLocalization of nitric oxide synthase indicating a neural role for nitric oxide.Nature19903477687701700301DSBredtPMHwangCEGlattCLowensteinRRReedSHSnyderCloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase.Nature19913517147181712077INMungrueDSBredtnNOS at a glance: implications for brain and brawn.J Cell Sci20041172627262915169833DBredtSSnyderIsolation of nitric oxide synthetase, a calmodulin-requiring enzyme.Proc Natl Acad Sci U S A1990876826851689048PWShaulRegulation of endothelial nitric oxide synthase: location, location, location.Annu Rev Physiol20026474977411826287SDimmelerIFlemingBFisslthalerCHermannRBusseAMZeiherActivation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.Nature199939960160510376603BGallisGLCorthalsDRGoodlettIdentification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002.J Biol Chem1999274301013010810514497CLowensteinCGlattDBredtSSnyderCloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme.Proc Natl Acad Sci U S A199289671167151379716DEBarananoSHSnyderNeural roles for heme oxygenase: contrasts to nitric oxide synthase.Proc Natl Acad Sci U S A200198109961100211572959JStamlerDSimonJOsborneS-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds.Proc Natl Acad Sci U S A1992894444481346070SRJaffreyHErdjument-BromageCDFerrisPTempstSHSnyderProtein S-nitrosylation: a physiological signal for neuronal nitric oxide.Nat Cell Biol2001319319711175752DTHessAMatsumotoS-OKimHEMarshallJSStamlerProtein S-nitrosylation: purview and parameters.Nat Rev Mol Cell Biol2005615016615688001RBAmsonMNemaniJ-PRoperchIsolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the Drosophilaseven in absentia gene.Proc Natl Acad Sci U S A199693395339578632996MNemaniGLinares-CruzHBruzzoni-GiovanelliActivation of the human homologue of the Drosophilasina gene in apoptosis and tumor suppression.Proc Natl Acad Sci U S A199693903990428799150J-PRoperchFLethroneSPrieurSIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21Waf1.Proc Natl Acad Sci U S A1999968070807310393949RLMargolisCARossExpansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases.Trends Mol Med2001747948211689312CARossMAPoirierProtein aggregation and neurodegenerative disease.Nat Med200410(suppl)S10S1715272267FSaudouSFinkbeinerDDevysMEGreenbergHuntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions.Cell19989555669778247SLiXLiAggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats.Hum Mol Genet199877777829536080JGHodgsonNAgopyanC-AGutekunstA YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.Neuron19992318119210402204HLiSHLiHJohnstonPFShelbourneXJLiAmino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity.Nat Genet20002538538910932179ALunkesKSLindenbergLBen-HaiemProteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions.Mol Cell20021025926912191472GSchillingAVSavonenkoAKlevytskaNuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice.Hum Mol Genet2004131599161015190011JCornettFCaoCEWangPolyglutamine expansion of huntingtin impairs its nuclear export.Nat Genet20053719820415654337ASawaENagataSSutcliffeHuntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts.Neurobiol Dis20052026727415890517BIBaeASawaSHSnyderGlyceraldehyde-3-phosphate dehydrogenase mediates the nuclear targeting of huntingin.Presented at: Society for Neuroscience 34th Annual Meeting; October 23-27, 2004; San Diego, CalifYLiPNowotnyPHolmansAssociation of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPDgene family.Proc Natl Acad Sci U S A2004101156881569315507493SHornMBSternThe comparative effects of medical therapies for Parkinson's disease.Neurology200463S7S1215477585MBYoudimPFRiedererA review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson's disease.Neurology200463S32S3515477584PJennerPreclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease.Neurology200463S13S2215477581FStocchiCWOlanowNeuroprotection in Parkinson's disease: clinical trials.Ann Neurol200353(suppl 3)S87S9712666101PALeWittClinical trials of neuroprotection for Parkinson's disease.Neurology200463S23S3115477583EKragtenILalandeKZimmermannGlyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl.J Biol Chem1998273582158289488718GAndringaRVvan OostenWUngerSystemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra.Eur J Neurosci2000123033304310971644PCWaldmeierAABoultonARCoolsACKatoWGTattonNeurorescuing effects of the GAPDH ligand CGP 3466B.J Neural Transm Suppl20006019721411205140PCWaldmeierWPSpoorenBHengererCGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease.Naunyn Schmiedebergs Arch Pharmacol200036252653711138845YSagotNToniDPerreletAn orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease.Br J Pharmacol200013172172811030721GAndringaARCoolsThe neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson's disease, the bilaterally MPTP-treated rhesus monkey.J Neural Transm Suppl20006021522511205142ERMatarredonaMMeyerRWSeilerHRWidmerCGP 3466 increases survival of cultured fetal dopaminergic neurons.Restor Neurol Neurosci200321293712808200GWCarlileRMEChalmers-RedmanNATattonAPongKLBBordenWGTattonReduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer.Mol Pharmacol20005721210617673MRHaraMBCascioASawaSHSnyderDeprenyl and its derivatives prevent S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase and inhibit GAPDH-SIAH1 apoptotic cascade.Presented at: Society for Neuroscience 35th Annual Meeting; November 12-16, 2005; Washington, DCMJBerridgeUnlocking the secrets of cell signaling.Annu Rev Physiol20056712115709950GHajnoczkyGCsordasMMadeshPPacherControl of apoptosis by IP3 and ryanodine receptor driven calcium signals.Cell Calcium20002834936311115374DRGreenGKroemerThe pathophysiology of mitochondrial cell death.Science200430562662915286356DRGreenApoptotic pathways: ten minutes to dead.Cell200512167167415935754XJiangXWangCytochrome c-mediated apoptosis.Annu Rev Biochem2004738710615189137DBoehningRLPattersonLSedaghatNOGlebovaTKurosakiSHSnyderCytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis.Nat Cell Biol200351051106114608362DBoehningDBvan RossumRLPattersonSHSnyderA peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways.Proc Natl Acad Sci U S A20051021466147115665074SAOakesLScorranoJTOpfermanProapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.Proc Natl Acad Sci U S A200510210511015613488SJHongTMDawsonVLDawsonNuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.Trends Pharmacol Sci20042525926415120492PJagtapCSzaboPoly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors.Nat Rev Drug Discov2005442144015864271JZhangVLDawsonTMDawsonSHSnyderNitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity.Science19942636876898080500HCHaSHSnyderPoly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion.Proc Natl Acad Sci U S A199996139781398210570184MJLEliassonKSampeiASMandirPoly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.Nat Med19973108910959334719BHellerZWangEWagnerInactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells.J Biol Chem199527011176111807744749BZingarelliALSalzmanCSzaboGenetic disruption of poly(ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury.Circ Res19988385949670921JCReedApoptosis-targeted therapies for cancer.Cancer Cell20033172212559172CDenicourtSFDowdyTargeting apoptotic pathways in cancer cells.Science20043051411141315353788LDWalenskyALKungIEscherActivation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.Science20043051466147015353804
TI - Messenger Molecules and Cell Death
JF - JAMA
DO - 10.1001/jama.295.1.81
DA - 2006-01-04
UR - https://www.deepdyve.com/lp/american-medical-association/messenger-molecules-and-cell-death-7s1JmKihS5
SP - 81
EP - 89
VL - 295
IS - 1
DP - DeepDyve
ER -