Research Report 2000 - MDC

Molecular Basis of
Congestive Heart
Failure
Rainer Dietz
Regulation of cardiac cell
growth and death
Frequently, congestive heart failure is
the clinical consequence of a
structural remodeling of the cardiac
phenotype, which is characterized by
two major components: maladaptive
growth and excessive death of
cardiomyocytes. Therefore, in order to
understand the molecular basis of
congestive heart failure one has to
elucidate the signaling cascade
controlling both the growth and death
of cardiac cells and describe their
interrelationship.
In contrast to cardiac growth where
numerous stimulating factors have
been identified, almost nothing is
known about the factors inducing
programmed death of cardiac cells.
Oxidative stress induced by oxygen
free radicals (ROS) is intimately
involved in the development of the
phenotype of the failing heart,
particularly since cardiomyocytes are
characterized by a high amount of
oxidative phosphorylation. Notably,
the lack of scavenging enzymes leads
to severe and lethal dilative
cardiomyopathy in knock-out mice.
In cell culture models we have been
able to characterize the intracellular
signaling cascade in cardiomyocytes
or vascular smooth muscle cells
exposed to oxidative stress ultimately
leading to apoptosis.
Furthermore, the role of ROS in
p53-induced apoptosis has been
investigated. The results show that not
Bax, but ROS, are the downstream
mediators of p53-induced apoptotic
signaling.
It is of great importance to understand
how terminally differentiated and
post-mitotic cells like cardiomyocytes,
can undergo programmed cell death,
since it is generally believed that
apoptosis is restricted to proliferating
cell types due to the fact that it only
can occur during a specific and
limited phase of the cell cycle. This
indicates that there has to be a tight
functional interrelationship between
the control of cell death, cell growth
and the cell cycle in cardiomyocytes.
Therefore, we recently investigated
the effect of overexpression of
E2F-1, which is a key factor in cell
cycle control, on the function of
cardiomyocytes. Cultured rat
cardiomyocytes infected with an
adenovirus harboring the E2F-1
cDNA start to initiate the cell cycle
machinery, as reflected by an
increased expression of S-phase
specific genes. However, the vast
majority of these cells undergo
apoptosis before entering the S-phase.
In contrast, cardiomyocytes
overexpressing E2F-1 overcome the
apoptotic signaling cascade and
initiate DNA-synthesis when insulinlike
growth factor I (IGF-I) is added
to the culture medium. This is of
particular interest since, in the heart,
IGF-I functions as the exclusive
downstream mediator of growth
hormone, which is currently used in
clinical trials in patients with
congestive heart failure.
In order to elucidate the cardiac cell
cycle control more systematically, we
have delevoped a myocardial cell-free
system where nuclei of terminally
differentiated cardiomyocytes are
exposed to cellular and/or nuclear
extracts of proliferating cells, leading
to the reinduction of cardiomyocyte
nuclear DNA synthesis.
Selected Publications
von Harsdorf, R., Hauck, L., Mehrhof,
F., Wegenka, U., Cardoso, C., and
Dietz, R. (1999) E2F-1
overexpression in cardiomyocytes
induces downregulation of p21CIP1
and p27KIP1 and release of active
cyclin-dependent kinases in the
presence of insulin-like growth factor
I. Circ. Res. 85, 128-136.
von Harsdorf, R., Li, P.-F., and Dietz,
R. (1999) Signaling pathways in
reactive oxygen species-induced
cardiomyocyte apoptosis. Circulation
99, 2934-2941.
Li, P.-F., Dietz, R., and von Harsdorf,
R. (1999) p53 regulates mitochondrial
membrane potential through reactive
oxygen species and induces
cytochrome c-independent apoptosis
blocked by Bcl-2. EMBO J. 18, 6027-
6036.
Li, P.-F., Maasch, C., Haller, H.,
Dietz, R., and von Harsdorf, R. (1999)
Requirement for protein kinase C in
reactive oxygen species-induced
apoptosis of vascular smooth muscle
cells. Circulation 100, 967-973.
Engel, F., Hauck, L., Cardoso C.,
Leonhardt, H., Dietz, R., and von
Harsdorf, R. (1999) A mammalian
myocardial cell-free system to study
cell cycle reentry in terminally
differentiated cardiomyocytes. Circ.
Res. 85, 294-301.
Structure of the Group
Group leader
Prof. Dr. Rainer Dietz
Scientists
Dr. Rüdiger v. Harsdorf
Dr. Ludger Hauck
Dr. Pei-Feng Li
Graduate students
Felix Engel
Felix Mehrhof
Technical assistants
Marlies Grieben
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