Review Article
“How Do Cardiomyocytes Die?” Apoptosis and Autophagic Cell Death in Cardiac Myocytes

https://doi.org/10.1016/j.cardfail.2006.02.002Get rights and content

Abstract

Background

Cell death constitutes one of the key events in biology. Historically, apoptosis and necrosis have been considered to represent the 2 fundamental forms of cell death. Apoptosis is a tightly regulated, energy-dependent process in which cell death follows a programmed set of events. Necrosis refers to the sum of degenerative changes that follow any type of cell death.

Methods and Results

The role of apoptosis in development of ischemic heart disease, hypertensive heart disease, and end-stage heart failure has been well documented. Recent evidence suggests the potential role of a third mechanism of cell death, autophagy, in loss of cardiac myocytes. Autophagic cell death has been recently documented in myocardial cells from hypertrophied, failing, and hibernating myocardium.

Conclusion

In this review, we will list the basic mechanisms of apoptosis and autophagic cell death and examine the recent developments in apoptosis and autophagic cell death as it pertains to cardiovascular disease.

Section snippets

Central Apoptotic Machinery

Apoptosis is mediated by 2 central pathways: the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway.28Fig. 1 illustrates the central parthways of apoptosis. Caspases, a subclass of cysteine proteases that cleave substrates after aspartic acid residues, are thought to be the central executioners of the apoptotic pathway.29 Caspases are highly conserved through evolution and can be found from humans all the way down to insects, nematodes, and hydra.30, 31, 32 In

Apoptosis in the Cardiovascular System

In the last decade, there has been increasing evidence suggesting the importance of apoptosis in the development and progression of cardiovascular disease. Apoptosis has been detected in the myocardium in a number of cardiac pathologies including hypoxia,73 ischemia followed by reperfusion, myocardial infarction, myocardial hypertrophy, and, more recently, in patients with end-stage heart failure.74, 75 Apoptosis has also been detected in atherosclerotic lesions of the vasculature.76

The Role of Autophagic Cell Death in Cardiomyocyte Loss

Autophagic cell death has been demonstrated in neurodegenerative disorders such as Parkinson's and Alzheimer's disease.136, 137 The role of autophagic cell death in heart muscle degeneration has largely remained obscure. Recent studies have demonstrated the existence of autophagic cell death in hypertrophied, failing, and hibernating myocardium.138, 139, 140, 141 Knaapen et al139 examined the cardiac tissue of patients in terminal stage of heart failure secondary to ischemic and dilated

The Possible Relationship Between the Ubiquitin-Proteasome System and Autophagic Cell Death

There are many lines of evidence that connect the autophagic machinery with the ubiquitin-proteasome pathway in cell death.142 The involvement and relationship between autophagic cell death and the ubiquitin-proteasome system in myocardial muscle degeneration/loss has remained relatively obscure. In an effort to examine the different diagnostic criteria of apoptotic cell death in cardiomyocytes, Knaapen et al139 studied the hypothesis of whether TUNEL labeling parallels caspase activation. The

Conclusion

Increasing evidence from both in vivo and in vitro studies suggest a strong role of apoptosis in the development of several cardiovascular diseases. Apoptosis inhibition may thus be a novel and exiting was to treat cardiovascular pathology. However, a significant number of questions regarding the relative contribution of apoptosis to cardiomyocyte death and its clinical relevance remain unclear. Apoptosis is not the only form of death leading to loss of cardiomyocytes, because recent evidence

References (143)

  • M.G. Grütter

    Caspases: key players in programmed cell death

    Curr Opin Struct Biol

    (2000)
  • L. Goyal

    Cell death inhibition: keeping caspases in check

    Cell

    (2001)
  • T. Suda et al.

    Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family

    Cell

    (1993)
  • R.M. Pitti et al.

    Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family

    J Biol Chem

    (1996)
  • N. Itoh et al.

    The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis

    Cell

    (1991)
  • H. Loetscher et al.

    Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor

    Cell

    (1990)
  • M.P. Boldin et al.

    A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain

    J Biol Chem

    (1995)
  • A. Ashkenazi et al.

    Apoptosis control by death and decoy receptors

    Curr Opin Cell Biol

    (1999)
  • K.M. Boatright et al.

    A unified model for apical caspase activation

    Mol Cell

    (2003)
  • X. Luo et al.

    Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors

    Cell

    (1998)
  • H. Li et al.

    Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis

    Cell

    (1998)
  • A. Gross et al.

    Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death

    J Biol Chem

    (1999)
  • D. Petrovic et al.

    Apoptosis and proliferation of cardiomyocytes in heart failure of different etiologies

    Cardiovasc Pathol

    (2000)
  • I. Vermes et al.

    Flow cytometry of apoptotic cell death

    J Immunol Methods

    (2000)
  • M. Rodriguez et al.

    Apoptosis: measurement and technical issues

    J Mol Cell Cardiol

    (2005)
  • S. Garg et al.

    Apoptosis and heart failure: clinical relevance and therapeutic target

    J Moll Cell Cardiol

    (2005)
  • L. Matturri et al.

    Characterization of myocardial hypertrophy by DNA content, PCNA expression and apoptotic index

    Int J Cardiol

    (2002)
  • A. Baldi et al.

    Apoptosis and post-infarction left ventricular remodeling

    J Mol Cell Cardiol

    (2002)
  • A. Abbate et al.

    Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure

    J Am Coll Cardiol

    (2003)
  • W.R. MacLellan et al.

    Death by design: programmed cell death in cardiovascular biology and disease

    Circ Res

    (1997)
  • S.W. Hetts

    To die or not to die: an overview of apoptosis and its role in disease

    JAMA

    (1998)
  • J.F.R. Kerr et al.

    Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics

    Br J Cancer

    (1972)
  • J. Searle et al.

    Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance

    Pathol Annu

    (1982)
  • D.S. Ucker

    Death by suicide: one way to go in mammalian cellular development?

    New Biol

    (1991)
  • L.M. Buja et al.

    Apoptosis and necrosis: basic types and mechanisms of cell death

    Arch Pathol Lab Med

    (1993)
  • G. Majno et al.

    Apoptosis, oncosis, and necrosis: an overview of cell death

    Am J Pathol

    (1995)
  • L.M. Buja et al.

    Modes of myocardial cell injury and cell death in ischemic heart disease

    Circulation

    (1998)
  • R.J. Collins et al.

    Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis

    Int J Radiat Biol

    (1992)
  • M.J. Arends et al.

    Apoptosis. The role of the endonuclease

    Am J Pathol

    (1990)
  • W. Bursch et al.

    The biochemistry of cell death by apoptosis

    Biochem Cell Biol

    (1990)
  • R. Gold et al.

    Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation

    Lab Invest

    (1994)
  • A.H. Wyllie

    Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

    Nature

    (1980)
  • M.C. Raff et al.

    Programmed cell death and the control of cell survival, lessons from the nervous system

    Science

    (1996)
  • N.K. Banda et al.

    Cross-linking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis

    J Exp Med

    (1992)
  • M.C. Bessis

    Death of a cell, 16-mm film

    (1958)
  • D.H. Hall et al.

    Neuropathology of degenerative cell death in Caenorhabditis elegans

    J Neurosci

    (1997)
  • P. Syntichaki et al.

    Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans

    Nature

    (2002)
  • W.A. Dunn

    Studies on the mechanisms of autophagy; formation of the autophagic vacuole

    J Cell Biol

    (1990)
  • N.A. Thornberry et al.

    Caspases: enemies within

    Science

    (1998)
  • I. Budihardjo et al.

    Biochemical pathways of caspase activation during apoptosis

    Annu Rev Cell Dev Biol

    (1999)
  • Cited by (0)

    View full text