Review
Molecular mechanisms of apoptosis in the cardiac myocyte

https://doi.org/10.1016/S1471-4892(01)00032-7Get rights and content

Abstract

Cardiac myocytes can undergo programmed cell death in response to a variety of insults and apoptotic elimination of myocytes from the adult myocardium can lead directly to cardiomyopathy and death. Although it remains to be shown that therapy specifically targeting apoptosis will improve the prognosis of ischemic heart disease or heart failure, a number of studies in the past year have shed light on potential ways to intervene in the process. Progress in the past year includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apotosis during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as β-adrenoceptor agonists, nitric oxide and calcineurin. Further evidence supports the pathophysiologic relevance of apoptosis in human heart disease. The tracking of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein (MAP) kinases p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminus kinase (JNK) in cardiac cell fate.

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 [6radical dotradical dot], 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:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

References (93)

  • J Gillespie-Brown et al.

    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

    (1995)
  • Y Wang et al.

    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

    (1998)
  • C Communal et al.

    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

    (2000)
  • K Mackay et al.

    Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia

    J Mol Cell Cardiol

    (2000)
  • Y.J Kang et al.

    Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases

    J Biol Chem

    (2000)
  • R Craig et al.

    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

    (2000)
  • H.E Hoover et al.

    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

    (2000)
  • Y Seko et al.

    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

    (1999)
  • R.J Davis

    Signal transduction by the JNK group of MAP kinases

    Cell

    (2000)
  • F Fiordaliso et al.

    Myocyte death in streptozotocin-induced diabetes in rats is angiotensin II-dependent

    Lab Invest

    (2000)
  • M Araki et al.

    Endothelin-1 as a protective factor against beta-adrenergic agonist-induced apoptosis in cardiac myocytes

    J Am Coll Cardiol

    (2000)
  • S Saito et al.

    Beta-adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes

    J Biol Chem

    (2000)
  • K Reiss et al.

    Insulin-like growth factor-1 receptor and its ligand regulate the reentry of adult ventricular myocytes into the cell cycle

    Exp Cell Res

    (1997)
  • K Kuwahara et al.

    Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes

    J Mol Cell Cardiol

    (2000)
  • W Wu et al.

    Expression of constitutively active phosphatidylinositol 3 kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells

    J Biol Chem

    (2000)
  • J.D Bisognano et al.

    Myocardial-directed overexpression of the human beta1-adrenergic receptor in transgenic mice

    J Mol Cell Cardiol

    (2000)
  • C.-F Wu et al.

    Atrial natriuretic peptide induces apoptosis in rat cardiac myocytes

    J Biol Chem

    (1997)
  • V Shneyvays et al.

    Induction of apoptosis in rat cardiocytes by A3 adenosine receptor activation and its suppression by isoproterenol

    Exp Cell Res

    (2000)
  • S Kotamraju et al.

    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

    (2000)
  • Q.M Chen et al.

    Hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes

    Arch Biochem Biophys

    (2000)
  • J Li et al.

    Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes

    J Biol Chem

    (1999)
  • B Zech et al.

    Mass spectrometric analysis of nitric oxide-modified caspase-3

    J Biol Chem

    (1999)
  • S.R Adderley et al.

    Glycoprotein IIb/IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase-3 activation

    J Biol Chem

    (2000)
  • T.A Holly et al.

    Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo

    J Mol Cell Cardiol

    (1999)
  • S Guerra et al.

    Myocyte death in the failing human heart is gender dependent

    Circ Res

    (1999)
  • F Sam et al.

    Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart

    Am J Physiol—Heart Circ Physiol

    (2000)
  • Y.T Zhou et al.

    Lipotoxic heart disease in obese rats: implications for human obesity

    Proc Natl Acad Sci USA

    (2000)
  • B.S Tea et al.

    Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats. Temporal regulation and spatial heterogeneity

    Hypertension

    (1999)
  • D Zhang et al.

    TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice

    Nat Med

    (2000)
  • M.O Hengartner

    The biochemistry of apoptosis

    Nature

    (2000)
  • K.C Wollert et al.

    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

    (2000)
  • G Filippatos et al.

    Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis

    Am J Physiol

    (1999)
  • D.P Nelson et al.

    Proinflammatory consequences of transgenic fas ligand expression in the heart

    J Clin Invest

    (2000)
  • T Nakamura et al.

    Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study

    Circulation

    (2000)
  • X Li et al.

    Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm

    Circulation

    (2000)
  • W Song et al.

    Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes

    Cardiovasc Res

    (2000)
  • Cited by (233)

    • Voluntary exercise training attenuated the middle-aged maturity-induced cardiac apoptosis

      2020, Life Sciences
      Citation Excerpt :

      Caspase-dependent apoptosis can be induced by two forms of apoptotic pathways, the extrinsic and intrinsic. The former one, Fas-dependent pathway is started by connecting the Fas ligand (FasL) or tumor necrosis factor-alpha (TNF-ɑ) to their receptors such as TNF receptor1 (TNFR1) and TNF receptor-associated factor 2 (TRAF2) on the cell membrane, causing the formation of a signal complex which induces death by gathering Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD) of the adaptor protein [11–13], resulting in the aggregation of pro-caspase-8 which could then activate caspase-8 [14]. This result leads to the splitting of pro-caspase-3, and further activates caspase-3, an autocatalyst executing the apoptotic program [15,16].

    View all citing articles on Scopus
    View full text