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Autophagic Degeneration and Death of

Cardiomyocytes in Heart Failure
Article in Autophagy July 2006
Impact Factor: 11.75 DOI: 10.4161/auto.2608 Source: PubMed

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6 authors, including:
Genzou Takemura

Hideshi Okada

Asahi University

Gifu University

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Available from: Hideshi Okada

Retrieved on: 19 May 2016

[Autophagy 2:3, 212-214, July/August/September 2006]; 2006 Landes Bioscience

Autophagic Degeneration and Death of Cardiomyocytes in Heart Failure

Addenda

ABSTRACT
Numerous cardiomyocytes were found to show autophagic vacuolar degeneration in
the UM-X7.1 hamster model of human dilated cardiomyopathy, and autophagy-related
proteinsi.e., ubiquitin, cathepsin D and Rab7were upregulated in those hearts.
Importantly, Evans blue-positive cardiomyocytes with leaky plasma membranes were also
positive for cathepsin D, suggesting a link between autophagic degeneration and cell
death. Treatment with granulocyte colony-stimulating factor (G-CSF) significantly
improved survival, cardiac function and remodeling in these animals, and such beneficial
effects were accompanied by a reduction in autophagy, an increase in cardiomyocyte
size, and a reduction in myocardial fibrosis. G-CSF-induced changes in molecular signaling
included activation of Akt and Stat3 (signal transducer and activator of transcription-3),
a reduction in the level of myocardial tumor necrosis factor-, and an increase in those
of matrix metalloproteinases. In contrast, neither cardiomyocyte apoptosis nor regeneration
of cardiomyocytes from bone marrow-derived cells was significant. It thus appears that
autophagic death and autophagy-dependent degeneration are important contributors to
loss of cardiomyocyte function in the cardiomyopathic hamster and that G-CSF exerts a
beneficial effect, mainly via an anti-autophagic mechanism.

KEY WORDS
autophagy, cardiomyopathy, cytokines, heart failure,
remodeling

IST

AUTOPHAGIC DEGENERATION AND DEATH IN HEART FAILURE

Dead and dying cardiomyocytes showing characteristics of autophagy have recently
been reported in heart failure caused by dilated cardiomyopathy, valvular heart disease,
hypertensive heart disease and chronic ischemia.1-5 Notably, the incidence of autophagic
cardiomyocytes in failing hearts was greater than the incidence of apoptotic cells, and thus
autophagy was suggested to be an important mechanism underlying the cardiomyocyte
dropout responsible for the worsening of heart failure. A direct connection between
autophagic degeneration and cell death, however, has not been definitively shown. That
said, we recently noted abundant and severe autophagic degeneration of cardiomyocytes
in the UM-X7.1 strain hamster, an animal model of human dilated cardiomyopathy, and
suggested that a linkage exists between autophagic degeneration and cell death based on
our observation of strong immunolabeling of cathepsin D in Evans blue dye-positive
cardiomyocytes with leaky plasma membranes.6
Cardiomyocyte death occurs via several pathways in heart failure and is thought to be
responsible for its development and progression (Fig. 1). We have observed cardiomyocytes
in which the cytoplasm has been replaced almost entirely with autophagic vacuoles (Fig. 2).
Sarcomeresi.e., the contractile apparatusremained only at the very edge of these cells.
It is highly plausible that, even if not dead, cardiomyocytes with such severe degenerative
changes cannot produce meaningful amounts of contractile power and thus contribute to
a worsening of cardiac function, which prompts us to consider the possibility that not only
autophagic death, but also autophagic degeneration, is important in the pathogenesis of
heart failure.

IEN

Addendum to:

OT
D

Previously published online as an Autophagy E-publication:

http://www.landesbioscience.com/journals/autophagy/abstract.php?id=2608

ON

Received 02/15/06; Accepted 02/15/06

.D

*Correspondence to: Hisayoshi Fujiwara; Second Department of Internal

Medicine; Gifu University School of Medicine; 1-1 Yanagido, Gifu 501-1194, Japan;
Tel.: +81.58.230.6520; Fax: +81.58.230.6521; Email: gifuim-gif@umin.ac.jp

CE

Second Department of Internal Medicine; Gifu University School of Medicine;

Gifu, Japan

RIB

UT
E

Genzou Takemura
Shusaku Miyata
Yukinori Kawase
Hideshi Okada
Rumi Maruyama
Hisayoshi Fujiwara*

BIO

SC

Autophagic Cardiomyocyte Death in Cardiomyopathic

Hamsters and Its Prevention by Granulocyte ColonyStimulating Factor

ES

S. Miyata, G. Takemura, Y. Kawase, Y. Li, H.

Okada, R. Maruyama, H. Ushikoshi, M. Esaki, H.
Kanamori, L. Li, Y. Misao, A. Tezuka, T. Toyo-Oka,
S. Minatoguchi, T. Fujiwara and H. Fujiwara

20

06

LA

ND

Am J Pathol 2006; 168:386-97

ROLE FOR AUTOPHAGIC CARDIOMYOCYTE DEATH IN HEART FAILURE

Autophagy is the type 2 programmed cell death that occurs during tissue and organ
development in order to eliminate unnecessary cells,7-9 but it also has survival-oriented
functions, protecting cells from stresses such as starvation.8-10 Autophagic cell death is
actually a morphological term derived from electron microscopy observations and denotes
a form of cell death in which abundant autophagic vacuoles are present in the cytoplasm.
But this definition tells us nothing about the pathophysiological function of autophagy in
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Autophagic Degeneration and Death of Cardiomyocytes in Heart Failure

Figure 1. Cardiomyocyte death pathways in heart failure. Three autophagy-related pathways are proposed. For details on the terms (oncotic and apoptosis
interruptus), please see references 13 and 14, respectively.

disease processes. Consequently, it is still undetermined whether an

abnormal increase in autophagy is the primary cause of cardiomyocyte
death in our animal model of heart failure. It is possible, for example,
that such autophagic cell death is simply the result of a failed
compensatory mechanism (decompensation of autophagy-mediated
survival machinery). A third possibility is seen with the heart failure
caused by Danon disease, where autophagic cardiomyocyte death
occurs through dysfunction of the autophagic process; a genetic
defect in the lysosomal protein Lamp-2 prevents digestion of
autophagolysosomes, resulting in the accumulation of autophagic
vacuoles within cardiomyocytes.11,12 Thus, in the context of heart
failure, autophagy-related death implies at least three pathophysiological settings (Fig. 1: i, programmed autophagic death; ii,
decompensated autophagic death (failure of survival-oriented
autophagy); and iii, autophagic death due to dysfunctional autophagy.
Given that autophagy has been observed in failing hearts, irrespective
of the etiology of the failure,1-6 we speculate that our animal model
showed decompensated autophagic death, but additional investigation
will be necessary to determine precisely the pathophysiological
setting of autophagic cardiomyocyte death in heart failure.

Figure 2. Electron micrographs showing severe vacuolar degeneration in a

cardiomyocyte from an untreated UM-X7.1 heart. Note that the cytoplasm is
almost entirely replaced by vacuoles. Arrows indicate the few remaining
myofibrils. Nucl, nucleus. *, a neighboring cardiomyocyte. Bar, 1 m.
Reprinted from Miyata et al., Am J Pathol 2006; 168:386-97 with permission
from the American Society for Investigative Pathology.

We found that treatment with granulocyte colony-stimulating

factor (G-CSF) significantly improved survival, cardiac function and
remodeling in an animal model of heart failure, and that these
beneficial effects were accompanied by a reduction in the incidence
of autophagy-associated structures, an increase in cardiomyocyte
size, and a reduction in myocardial fibrosis. In addition, observed
G-CSF-induced changes in downstream molecular signals included

activation of Akt and Stat3 (signal transducer and activator of

transcription-3), a reduction in myocardial levels of tumor necrosis
factor-, and increased levels of matrix metalloproteinases. On the
other hand, neither cardiomyocyte apoptosis nor regeneration of
cardiomyocytes from bone marrow-derived cells was significant in
the present model and neither was affected by G-CSF.
What then is the primary mechanism via which G-CSF exerts its
marked benefits on heart failure? At its simplest, the autophagic

MECHANISM OF ACTION OF G-CSF IN HEART FAILURE

www.landesbioscience.com

Autophagy

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Autophagic Degeneration and Death of Cardiomyocytes in Heart Failure

process can be divided into two steps: (1) production of autophagic

vacuoles and (2) digestion of those vacuoles. In that context, there
may be three ways to inhibit accumulation of autophagic vacuoles
within the cells: (i) inhibition of step 1; (ii) acceleration of step 2;
and (iii) prophylaxis. In the event that the autophagy seen in heart
failure is survival-oriented, inhibition of step 1 would be harmful to
the cell. On the other hand, to accelerate step 2 may not only prevent
accumulation of the vacuoles, but also promote efficient recycling of
molecules for survival, and would thus seem to be a promising
method to inhibit autophagic vacuole accumulation, even in the case
of survival-oriented autophagy. Indeed, acceleration of step 2 may be
particularly beneficial in cases of lysosomal dysfunction, such as
Danon disease. Finally, prophylaxis means providing conditions that
are favorable enough that cells do not need autophagy operating. If
in our model cardiomyocytes underwent decompensated autophagic
death, G-CSF could act either by accelerating step 2 of the autophagic
process or by preventing cells from needing to execute autophagy in
the first place (prophylaxis). We did not examine the functional
status of the processes involved in digestion of autophagic vacuoles
in our animal model, but that question should be addressed in future
analyses of autophagic function in heart failure.
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