ReviewMolecular mechanisms of apoptosis in the cardiac myocyte
Introduction
The Greek word apoptosis was adopted by Wyllie and colleagues [1] to suggest the relationship between the autumnal shedding of leaves and the programmed death of cells from tissues. Although apoptosis was originally defined by morphological criteria, it is probably best defined functionally: as a stepwise, tightly regulated mechanism for eliminating damaged or superfluous cells without harming their healthy neighbors. Controlled deletion of cells serves many useful functions in development and during stress to ensure the survival and integrity of the organism; however, when apoptosis is not balanced by cell replacement in the adult myocardium, functional impairment can result.
The role of apoptosis in myocardial diseases has attracted considerable attention as a potentially reversible cause of cardiac functional deterioration. A large body of evidence now supports the ability of myocytes to activate and die by this process in response to a range of stresses including hypoxia, free radical stress, viral infection, adrenergic overstimulation and work overload [2]. This review will focus primarily on studies published in the past year that have provided insight into the molecular mechanisms of apoptosis in the postnatal cardiac myocyte and will report on the current status of anti-apoptotic therapy in experimental models of acute and chronic heart disease.
Section snippets
The heartbreak of apoptosis
Cardiac myocytes possess the necessary apparatus for cellular suicide and activate the process in response to a variety of stresses. Apoptosis occurs concomitantly with necrosis in the infarcted and reperfused myocardium [3], in the endstage failing heart [4], in postinfarction left ventricular remodeling [5], in diabetes [6], and during the regression of hypertrophy [7]. Direct evidence that cardiac myocyte apoptosis is sufficient to cause heart failure has emerged from genetically manipulated
The death receptor
Two independent pathways lead to the induction of apoptosis, with limited crosstalk between the two (Fig. 1; [12]). The type I or ‘extrinsic’ apoptotic pathway is mediated by external factors that bind to members of the death receptor superfamily, of which Fas (also known as APO-1/CD95) and TNFR1 (tumor necrosis factor-α receptor-1) are prominent examples. These transmembrane receptors feature cytosolic ‘death domains’ that become activated by proximity to each other. Specific binding by Fas
The mitochondrion
The second major pathway for apoptosis is the ‘intrinsic’, or type II, mitochondria-dependent pathway (Fig. 1). The mitochondria contain a number of highly lethal substances that can initiate apoptosis when released into the cytosol. One of these is the small electron transporter cytochrome c. Under conditions that remain mysterious, cytochrome c is released from mitochondria and forms a complex with procaspase 9 and its cofactor APAF-1 (apoptotic protease-activating factor-1). In the presence
The Bcl-2 proteins
The mitochondrion is the main site of action for members of the apoptosis-regulating protein family exemplified by Bcl-2. Bcl-2 proteins fall into three classes, of which one is anti-apoptotic and the others pro-apoptotic. Many Bcl-2 proteins are thought to associate with and regulate PT pore proteins, such as the voltage-dependent anion channel (VDAC) [12]. Pro-apoptotic and anti-apoptotic members of the family appear to interact with and neutralize each other, so that the relative balance of
Mitogen-activated protein kinases
Members of the MAP kinase family, including ERK-1 and -2, JNK-1 and -2 and p38MAP kinases, play an important role in cell fate decisions [37] and have been implicated in survival signaling in cardiac myocytes, particularly in response to oxidative stress 38., 39., 40., 41., 42.. Activation of various combinations of MAP kinases occurs in response to ischemia–reperfusion, β-adrenergic stimulation, NO and anthracycline exposure. Combinatorial activation of MAP kinase-dependent pathways is the
Cardiac myocyte growth signals and apoptosis
Growth factors mediate both proliferative and survival responses in many cell types. In contrast, few of the physiological agents known to induce myocyte growth are unambiguously pro-life or pro-death, and it is unlikely that cardiac growth per se represents an apoptotic signal. Hemodynamic loading, probably the most important signal for myocyte growth, initiates both pro-apoptotic and anti-apoptotic cell signaling 9, 40.. The same mixed messages emanate from other hypertrophic agents. Only a
Oxidative stress, hypoxia and apoptosis
Protracted loss and sudden restoration of myocardial blood flow (ischemia and reperfusion, respectively) are powerful stimuli for apoptosis as well as cell death by other means 77, 78.. Most sources of oxidative stress are potent pro-apoptotic agents 22, 79., 80, 81.. The relative importance of other components of ischemia (hypoxia, glucose depletion, and acidosis) in apoptosis are only now beginning to become clear.
Several studies, including our own, indicate that severe hypoxia by itself is
Nitric oxide and apoptosis
NO, a free radical gas that participates in a wide range of signal transduction pathways in the cell, is directly lethal to both neonatal and adult cardiac myocytes 29., 55., 84., 85.. Cytokines including TNF-α, interleukin (IL)-1β and interferon (IFN)γ may be highly pro-apoptotic through the induction of iNOS and subsequent production of NO 18., 29., 84.. Cells induced to express iNOS can produce micromolar amounts of NO [86], and in the presence of superoxide can produce peroxynitrite. The
Conclusions
Interest in apoptosis as a target for therapy in the setting of cardiovascular disease is likely to increase as new mechanisms and effectors are uncovered. The near future is likely to provide a better understanding of the importance of apoptosis in the clinical effects of pharmaceuticals [92] and of the value of apoptosis as a therapeutic target, or at least as a marker for pathological stress, in heart disease. The use of anti-apoptotic agents in the setting of acute myocardial infarction
Acknowledgements
The authors apologize to their many colleagues whose important papers were not individually cited here, for reasons of space. We thank the Miami Heart Research Institute for their ongoing support of our work. This work was also supported by grants from the National Institutes of Health (NHB and KAW) and by a fellowship from the American Heart Association Florida/Puerto Rico Affiliate (PA). NHB is an Established Investigator of the American Heart Association.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
References (93)
- et al.
Cell death: significance of apoptosis
Int Rev Cytol
(1980) - et al.
Apoptosis in heart failure
Prog Cardiovasc Dis
(1998) - et al.
Apoptosis is initiated by myocardial ischemia and executed during reperfusion
J Mol Cell Cardiol
(2000) - et al.
Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress
Cell
(1999) - et al.
Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device
J Card Fail
(1999) - et al.
Apoptosis and proliferation of cardiomyocytes in heart failure of different etiologies
Cardiovasc Pathol
(2000) - et al.
Inhibition of p53 function prevents renin-angiotensin system activation and stretch-mediated myocyte apoptosis
Am J Pathol
(2000) - et al.
Upregulation of the Bcl-2 family of proteins in end stage heart failure
J Am Coll Cardiol
(2000) - et al.
Influence of age on hypoxia/ reoxygenation-induced DNA fragmentation and bcl-2, bcl-xl, bax and fas in the rat heart and brain
Mech Ageing Dev
(1999) - et al.
Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease
J Mol Cell Cardiol
(1999)
The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes
J Biol Chem
Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells
J Biol Chem
p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta-adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation
J Biol Chem
Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia
J Mol Cell Cardiol
Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases
J Biol Chem
p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system
J Biol Chem
alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response
J Biol Chem
Pulsatile stretch activates mitogen-activated protein kinase (MAPK) family members and focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes
Biochem Biophys Res Commun
Signal transduction by the JNK group of MAP kinases
Cell
Myocyte death in streptozotocin-induced diabetes in rats is angiotensin II-dependent
Lab Invest
Endothelin-1 as a protective factor against beta-adrenergic agonist-induced apoptosis in cardiac myocytes
J Am Coll Cardiol
Beta-adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes
J Biol Chem
Insulin-like growth factor-1 receptor and its ligand regulate the reentry of adult ventricular myocytes into the cell cycle
Exp Cell Res
Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes
J Mol Cell Cardiol
Expression of constitutively active phosphatidylinositol 3 kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells
J Biol Chem
Myocardial-directed overexpression of the human beta1-adrenergic receptor in transgenic mice
J Mol Cell Cardiol
Atrial natriuretic peptide induces apoptosis in rat cardiac myocytes
J Biol Chem
Induction of apoptosis in rat cardiocytes by A3 adenosine receptor activation and its suppression by isoproterenol
Exp Cell Res
Doxorubicin- induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen—role of reactive oxygen and nitrogen species
J Biol Chem
Hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes
Arch Biochem Biophys
Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes
J Biol Chem
Mass spectrometric analysis of nitric oxide-modified caspase-3
J Biol Chem
Glycoprotein IIb/IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase-3 activation
J Biol Chem
Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo
J Mol Cell Cardiol
Myocyte death in the failing human heart is gender dependent
Circ Res
Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart
Am J Physiol—Heart Circ Physiol
Lipotoxic heart disease in obese rats: implications for human obesity
Proc Natl Acad Sci USA
Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats. Temporal regulation and spatial heterogeneity
Hypertension
TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice
Nat Med
The biochemistry of apoptosis
Nature
The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system:relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes
Circulation
Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis
Am J Physiol
Proinflammatory consequences of transgenic fas ligand expression in the heart
J Clin Invest
Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study
Circulation
Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm
Circulation
Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes
Cardiovasc Res
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