doi:10.1016/j.bbamcr.2007.01.011


Biochimica et Biophysica Acta 1773 (2007) 480–482
www.elsevier.com/locate/bbamcr
Review

Cardiomyocyte necrosis: Alternative mechanisms, effective interventions

Nektarios Tavernarakis ⁎

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Vassilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece

Received 10 January 2007; accepted 22 January 2007
Available online 28 January 2007
Abstract

Necrotic death of cardiac myocytes is a major contributor to heart failure associated with several cardiac pathologies such as ischemia and
reperfusion injury. Preventing cardiomyocyte necrosis is an important challenge towards the development of effective strategies, aiming to battle
cardiovascular disorders. While, necrotic cell death was traditionally considered a passive and chaotic process, emerging evidence indicates that
specific molecular mechanisms underlie cellular destruction during necrosis. Elucidation of these mechanisms will facilitate therapeutic
intervention against heart failure.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Ischemia; Lipid; Mitochondria; Necrotic cell death; Oxidative stress; Peroxidation; Reperfusion
Three major types of cell death have been described in
diverse organisms, apoptosis autophagic vacuolation and
necrosis [1–3]. Although necrosis has been associated with
extensive cell loss that accompanies many devastating human
pathologies such as stroke, heart diseases and several
neurodegenerative conditions, the biochemical pathways med-
iating the necrotic destruction of cells have long remained
obscure. One of the main reasons why molecular characteriza-
tion of necrosis lagged considerably behind that of the other two
types of cell death has been the – until recently – prevailing
notion that necrosis is a catastrophic type of cell death that is
uncontrollable and does not involve any specific mechanisms
[4]. Why study necrosis if there is nothing there to find?

However, this concept is being overturned by findings in
organisms ranging from the lowly nematode worm Caenor-
habditis elegans to mammals, which reveal that necrotic death
is carried out by conserved cellular processes. Genetic and
biochemical dissection of these processes shows that, rather
than being a disorganized breakdown of the cell, necrosis is
orchestrated and executed by appropriate mechanisms, depend-
ing on the death initiating stimulus [5]. What triggers necrotic
cell death? Cells suffer necrosis when exposed to excessive
stress and adverse environmental conditions such as lack of
⁎ Tel.: +30 2810 39 1066; fax: +30 2810 39 1067.
E-mail address: tavernarakis@imbb.forth.gr.

0167-4889/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbamcr.2007.01.011
oxygen or essential nutrients (i.e. in the case of ischemia during
a heart attack or following stroke), elevated temperature, toxic
or corrosive compounds and excessive mechanical strain (i.e. in
the case of trauma). In addition to external predicaments,
necrotic cell death can also be inflicted by genetic abnormalities
(i.e. deleterious gene mutations in neurodegenerative disorders).

An important corollary of investigating the mechanisms of
necrosis, highly relevant to human health, is the emerging
potential for prevention or therapeutic intervention. Although,
once induced, necrotic cell death was considered inevitable, the
recent identification of signaling pathways and genes required
for cell demise offers opportunities for the development of
educated intervention strategies, designed to counter or
ameliorate pathological conditions with a significant necrosis
component. The study by Casey, Arthur and Bogoyevitch holds
such a promise for heart damage following acute myocardial
infarction and ischemia [6]. In this and other cardiac
pathologies, ensuing cardiomyocyte cell death is a major
contributor to heart dysfunction and failure. Oxidative stress
due to accumulation of reactive oxygen species (ROS) has been
implicated in triggering cell death [7]. Casey, Arthur and
Bogoyevitch show that high hydrogen peroxide (H2O2)
concentration causes a pattern of late-onset death of neonatal
cardiomyocytes in culture. Dying cells exhibit ultrastructural
characteristics of necrosis, with delayed leakage of lactate
dehydrogenase (LDH), which signifies compromise of plasma

mailto:tavernarakis@imbb.forth.gr
http://dx.doi.org/10.1016/j.bbamcr.2007.01.011


481N. Tavernarakis / Biochimica et Biophysica Acta 1773 (2007) 480–482
membrane integrity. Lack of caspase-3 activation, which occurs
during apoptosis, further suggests that cardiomyocyte death is
not apoptotic.

One of the traditional hallmarks of ROS-initiated cell death
is mitochondrial dysfunction and energy depletion [8]. This is
manifested by opening of the mitochondrial permeability
transition pore (MPTP), the collapse of the mitochondrial
membrane potential (MMP) and the concomitant drop in ATP
production [9–11]. These events set in motion a battery of cell
destruction cascades and at the same time, limit the capacity of
the cell for energy production. Intriguingly, Casey, Arthur and
Bogoyevitch demonstrate that necrotic death of cardiomyocytes
under oxidative stress does not involve opening of MPTP of
loss of MMP. Furthermore, cellular ATP content is only
transiently reduced upon treatment with H2O2 and in fact, it
later recovers to close the normal levels. These observations
suggest that death is not merely the result of an inescapable
energy crisis that undermines cell viability.

What then is killing the cells experiencing oxidative stress
induced by H2O2? Calcium-activated calpain proteases and
lysosomal, acidic aspartyl proteases, which are required for
necrotic cell death in C. elegans and mammalian neurons
[12,13], do not appear to be involved. Rather, alternative
mechanisms of cell destruction might be in operation, in this
experimental paradigm. Casey, Arthur and Bogoyevitch show
that lipid peroxidation is an important contributing factor. First,
Fig. 1. Membrane lipid peroxidation contributes to oxidative stress-induced cell dea
antioxidant defenses and causes peroxidation of plasma or other membrane lipids. P
hydroperoxides and aldehyde byproducts such as 4-hydroxynonenal (HNE). In turn, H
transporters and pumps [20,21]. The cumulative effect of such modifications is cell
leukemia inhibitory factor, ROS: reactive oxygen species, SOD: superoxide dismuta
lipid peroxidation is significantly increased upon exposure of
cardiac myocytes to H2O2 and second, inhibition of lipid
peroxidation by the vitamin E analogue trolox or by the iron
chelator dipyridyl prevents cell death (Fig. 1).

What cellular processes could be stimulated or augmented to
fortify cells against cell death? Previous studies have shown that
two hypertrophic agents, endothelin-1 (ET-1) and leukemia
inhibitory factor (LIF) protect cardiomyocytes under oxidative
stress from apoptotic death [14,15]. Interestingly, Casey, Arthur
and Bogoyevitch have found that peroxiredoxin 3 and alpha-B
crystallin are among the proteins with increased abundance after
treatment of cardiomyocytes with ET-1, whereas treatment with
LIF increases the abundance of Cu/Zn superoxide dismutase
and Hsp20 and 60 [16]. Therefore, by provoking such
proteomic profile changes, these hypetrophic agents may
strengthen antioxidant and stress defenses of cells. Indeed,
pretreatment of cardiomyocytes with ET-1 or LIF inhibits
necrosis induced by H2O2 (Fig. 1).

The totality of these findings highlight the feasibility of
formulating effective interventions against necrotic cell death
associated with human pathologies. This is a particularly
exciting prospect, given that ischemic diseases of the heart,
kidney and brain as well as neurodegenerative disorders are
among the primary causes of disability, morbidity and mortality.
Numerous studies utilizing an assortment of experimental
systems converge to the conclusion that necrosis is not simply
th. Excessive accumulation of reactive oxygen species (ROS) saturates cellular
eroxidation compromises the integrity of these membranes and generates lipid
NE may perturb ion homeostasis by interfering with the function of ion channels
injury and ultimately, death. ET-1: endothelin-1, HNE: 4-hydroxynonenal, LIF:
se.



482 N. Tavernarakis / Biochimica et Biophysica Acta 1773 (2007) 480–482
the decadent and inexorable fate of a cell otherwise not meant to
die [1,17,18]. Understanding the intricacies of necrosis inflicted
by diverse initiators will shed light into the biochemical events
that transpire during cell death. The molecules enacting these
biochemical events are effectors of necrosis and should, in
principle, constitute excellent targets for drug development [19]
and other methodologies designed to ameliorate or block
pathological cell death.
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	Cardiomyocyte necrosis: Alternative mechanisms, effective interventions
	References