Contribucion de La Sepsis

Basic Res Cardiol 93: 71 – 84 (1998)
© Steinkopff Verlag 1998 FOCUSSED ISSUE: APOPTOSIS
B. Bartling Contribution of myocyte apoptosis

J. Holtz
D. Darmer to myocardial infarction?
with random nuclear DNA fragmentation. Such description,

Introduction by contrast, appears to imply that apoptosis and necrosis were
Continuously ongoing loss of cardiac myocytes by apoptosis, two completely separated, mutually exclusive forms of cell
resulting from myocyte stretch due to hemodynamic overload, death.
has been hypothesized as contributing to the progression of Therefore, surprise and scepticism were triggered by
myocardial dysfunction in chronic heart failure (13). In sup- reports claiming that myocyte apoptosis contributes to
port of this hypothesis, it has been shown: myocardial infarction (Fig. 1). Three constellations resulting
a) that cardiac myocytes physiologically do recruite their in myocyte death with signs of apoptosis have been described
genetic program of apoptosis (e.g., for adjustment of the in myocardial ischemia: a) sporadic death of myocytes, scat-
myocardial cellular stoichiometry during cardiac develop- tered in the viable myocardium remote from the ischemic area
ment; 65, 71), and reminiscent to stretch-induced myocyte apoptosis in other
b) that stretch of adult mammalian myocardium induces forms of overload-induced heart failure (20, 89, 116); b) post-
myocyte apoptosis in vitro (21), and ischemic reperfusion-induced myocyte apoptosis in the border
c) that signs of apoptosis are present in left ventricles in zone of infarcts (45, 50, 124, 148, 152) which might partially
chronic heart failure of humans (108, 115, 133) or experi- result from the action of cytokines and activated blood phago-
mental animals (see 16, 44, 96). cytes on myocytes, damaged by the preceding ischemia; c)
Certainly, the suggestion of an overload-inducible program myocyte death with signs of apoptosis in the core of an
of myocyte losses, further enhancing the overload, is an attrac- ischemic myocardial area with permanently occluded coronary
tive concept explaining the progressive nature of terminal arteries or in fresh myocardial infarctions (6, 11, 45, 61, 70).
cardiac failure. However, this concept is still far from being The myocyte death in permanently ischemic myocardium
unequivocally established: the mechanisms and the elements (constellation c) is traditionally considered as necrosis, since
of the apoptotic program in myocytes of the failing heart are the release of cytosolic constituents from the cardiocytes (such
largely unknown. Reviews on apoptosis in general (28, 54, as creatine kinase MB, troponin-T or other proteins) is a reli-
127, 133, 161) tend to describe apoptosis by delineation ver- able indicator of ischemic cell loss or infarct size and of the
sus necrotic cell death: apoptotic cell death with cytosolic subsequent risk for cardiovascular mortality (1, 47, 55, 74, 90,
proteolysis and with enzymatic cleavage of nuclear DNA into 95, 113, 128). Therefore, this “necrotic” release cannot be con-
oligonucleosome sized fragments in the presence of a func- sidered as a marginal epiphenomenon of “mostly apoptotic
tionally intact cell membrane, and necrosis with accidental ischemic” myocyte death.
collapse of cellular homeostasis, compartimentalization, and However, is it possible that oligonucleosome-sized DNA
cell membrane integrity with release of cytosolic material and fragmentation (11, 45, 61, 70), even in the presence of not yet
damaged cardiocyte cell membranes (Fig. 1), is an irrelevant
epiphenomenon of necrotic cell death? There is some debate
as to whether fragmentation of DNA into apoptosis-typical
B. Bartling (Y) · J. Holtz · D. Darmer “ladders” is a reliable indicator of apoptosis (29, 114, 150) and
Institut für Pathophysiologie
Martin-Luther-Universität Halle-Wittenberg whether DNA-ladders also might partially result from post-
BRC 075
Magdeburger Straße 18 mortal manipulation of tissue samples with ischemic damage.

D-06097 Halle/Saale Considering apoptotic signs in ischemic cardiocytes as an
72 Basic Research in Cardiology, Vol. 93, No. 2 (1998)
© Steinkopff Verlag 1998
Fig. 1 Features of myocyte death

in rats with coronary occlusion.
Groups of rats with coronary
occlusion were sacrificed at dif-
ferent intervals after occlusion;
left ventricular myocytes were
analyzed for nuclear apoptosis
(TUNEL assay) and cell mem-
brane damage (labeling by car-
diac myosin-specific antibody
injected prior to sacrifice). Note
that cardiomyocytes with signs of
apoptosis (TUNEL-positive
nuclei, but intact sarcolemma),
with signs of necrosis (damaged
cell membrane, but no nuclear
TUNEL labeling) and with com-
bined features were detected
(drawn from data in reference
70).
irrelevant and partially artefactual epiphenomenon would abrogated or decreased oxygen supply is a potential damaging
imply that some final steps of the apoptotic program might be factor of myocardial ischemia and results in many functional
activated by chance during damage-induced necrosis and by changes:
postmortal processes, but that this activation is without rele- O uncoupling of H+ proton motive force from the ATP syn-
vance for the extent of the ischemic damage in vivo. thesis,
In contrast to this view, we will discuss here recent data O cytosolic accumulation of Ca2+ and Na+ ions due to inacti-
which – in our opinion – clearly indicate that apoptotic steps vated ATP-dependent ion channels (97),
do have some relevance in ischemic myocyte necrosis. Such O raised activity of Ca2± dependent enzymes, such as PLA2
data on the protective effect of antiapoptotic interventions in and PLC (126) or endonucleases (149),
ischemia-related protocols in cardiomyocytes and neurons are O abnormal production of lactate provoking intracellular
summarized in Table 1. Furthermore, we will argue that the acidosis with concomitant increase in inorganic phosphate
efforts towards a strict separation of necrosis and apoptosis (Pi),
might be counterproductive for the understanding of ischemic O exhaustion of the radical defence systems, such as super-
myocyte losses and for the development of strategies mini- oxide dismutase (SOD) activity (43),
mizing those losses. For this discussion, consideration of some O hydrogen peroxide-induced peroxidation of membrane
features of ischemic myocyte necrosis in comparison with phospholipids which can be hydrolyzed by PLA2 into free
apoptosis might be helpful, although both processes are fatty acids and lysophospholipids (3, 154),
incompletely understood. O subsequent to cytosolic Ca2+ accumulation, an increase in
mitochondrial Ca2+ (66) as consequence of membrane
defects caused by accumulation of toxic metabolites, reac-
tive oxygen species and lysophospholipids (42), resulting
Ischemic cardiomyocyte necrosis in water entry, mitochondrial swelling (35), and collapse of
mitochondrial membrane potential, and
During ischemia-induced myocyte cell death, there are early O specific mitochondrial DNA destruction (99).
changes in mitochondrial shape and function and the cells are During reperfusion and reoxygenation, the Ca2+ overload
soon unable to maintain cellular homeostasis. The plasma persists (104), and the formation of reactive oxygen species is
membrane-mediated regulation of osmotic pressure is dis- not only increased by NADPH oxidase and myeloperoxidase,
turbed and the myocyte swells and ruptures. The consequence both activated in invaded neutrophils, but also by xanthin oxi-
is a loss of cytosolic components, resulting in activation of dase (41, 86, 120). Additionally, the ATP/ADP relation is
inflammatory reactions and in increased plasma concentra- reduced due to increased CPK activity (59). Although early
tions of cardiomyocyte-specific proteins. Since cardiomy- reperfusion damage is demonstrable in experimental models,
ocytes generate ATP for maintenance of both contractile func- long-term reperfusion is believed to improve myocyte sur-
tion and ionic homeostasis by oxidative phosphorylation, vival and the clinical conditions in patients with myocardial

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Basic Res Cardiol 93: 71 – 84 (1998)

© Steinkopff Verlag 1998 FOCUSSED ISSUE: APOPTOSIS

B. Bartling Contribution of myocyte apoptosis

with random nuclear DNA fragmentation. Such description,

Magdeburger Straße 18 mortal manipulation of tissue samples with ischemic damage.

Fig. 1 Features of myocyte death

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