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Franz-Volhard-Klinik
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Medizinische Fakultät der
Humboldt-Universität zu Berlin
Campus Berlin-Buch
am Max-Delbrück-Centrum für
Molekulare Medizin
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Molecular Basis of Congestive Heart
Failure
Structure of the group
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head:
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Ruediger von Harsdorf, M.D.
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co-workers:
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Rainer Dietz, M.D.
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Ludger Hauck, Ph.D.
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Peifeng Li, Ph.D.
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Felix Mehrhof, M.D.
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Joerg Mueller, Ph.D.
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Martin Bergmann, M.D.
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Mikael Skatchkov, Ph.D.
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Jianping Gao, M.D.
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Jincheng Li, M.D.
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Felix Engel, Ph.D. student
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Marlies Grieben, technical assistant
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contact:
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phone: ++49 30 9406 3146
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email: [email protected]
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Background
The focus of our recent studies is the characterization of
regulation of growth and death of cardiomyocytes. We hypothesize that
activation of cell death signalling cascades not only may result in
apoptosis, but may be integral part of the maladaptive process
characterizing the phenotype of the failing myocardium. Likewise,
maladaptive growth and/or apoptosis may involve the incomplete
re-activation of postnatally silenced cell cycle activating cascades.
Therefore, the understanding of the molecular basis of congestive
heart failure necessitates the investigation of the mechanisms
regulating hypertrophy and proliferation as well as death of
cardiomyocytes, and in particular their intercalation.Furthermore, we
hypothesize that oxidative stress plays a pivotal role in the
development of the failing myocardium in part by activating
pro-apoptotic signalling events in cardiomyocytes and proliferation
of cardiac interstitial cells. Therefore, assessing the role of
reactive oxygen species in control of growth and death of
cardiomyocytes and the quantitative assessment of oxidative stress in
heart failure patients is in the focus of our studies.
Results
We characterized in detail the intracellular signalling cascade
involved in apoptosis of cardiomyocytes induced by oxidative stress
(v.
Harsdorf et al. 1999, Circulation 99: 2934-2941).
Interestingly, the apoptotic stimulus of oxidative stress in
cardiomyocytes is not shared by cardiac fibroblasts (Li
et al. 1999, FEBS lett 448: 206-210). In comparison,
the role of oxidative stress in cell death of vascular smooth muscle
cells is even more complex (Li
et al., 1997, FEBS lett 404: 249-252; Li
et al., 1997, Circulation 96: 3602-3609) and appears
to involve protein kinase C (Li
et al. 1999, Circulation 100: 967-973). In general,
the intracellular generation of reactive oxygen species may be
integral part of apoptotic cell death (Li
et al. 1999, EMBO Journal 18: 6027-6036). Apoptosis is
the consequence after forced overexpression of the transcription
factor E2F1- in cardiomyocytes (v.
Harsdorf et al., 1999, Circ Res 85: 128-136)
indicating an interaction between signals regulating apoptosis and
proliferation in cardiomyocytes. Therefore, we developed a novel in
vitro assay to study cell cycle and/or growth control in
cardiomyocytes more systematically (Engel
et al. 1999, Circ Res 85: 294-301).
Perspective
Our future studies are aimed at the identification of key players
in cardiomyocytes controlling apoptosis and/or proliferation and
their intercalation with one another and particularly with classical
growth signalling cascades which could become specific targets for
novel therapy regimens in congestive heart failure.
Funding
Our work is supported in part by the Deutsche
Forschungsgemeinschaft (DFG), the Bundesministerium für
Forschung und Technik (BMBF) and the Max-Delbrueck-Center for
Molecular Medicine (MDC).
List of selected publications
- Li P, Dietz R, von Harsdorf R: p53 regulates mitochondrial
membrane potential through reactive oxygen species and induces
cytochrome c-independent apoptosis blocked by Bcl-2. EMBO
J 1999, 18: 6027-6036
- Li P, Maasch C, Haller H, Dietz R, von Harsdorf R: Requirement
of protein kinase C in reactive oxygen species-induced apoptosis
of vascular smooth muscle cells. Circulation
1999, 100: 967-973
- Engel F, Hauck L, Cardoso C, Leonhardt H, Dietz R, von
Harsdorf R: A mammalian myocardial cell-free system to study cell
cycle re-entry in terminally differentiated cardiomyocytes.
Circ
Res 1999, 85: 294-301
- von Harsdorf R, Hauck L, Mehrhof F, Cardoso C, Dietz R: 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 1999, 85: 128-136
- von Harsdorf R, Li P, Dietz R: Signaling pathways in reactive
oxygen species-induced cardiomyocyte apoptosis. Circulation
1999, 99: 2934-2941
- Li P, Dietz R, von Harsdorf R: Superoxide induces apoptosis in
cardiomyocytes, but proliferation and expression of transforming
growth factor-ß1 in cardiac fibroblasts. FEBS
lett 1999, 448: 206-210
- Li P, Dietz R, von Harsdorf R: ifferential effect of hydrogen
peroxide and superoxide anion on apoptosis and proliferation of
vascular smooth muscle cells. Circulation
1997; 96: 3602-3609
- von Harsdorf R, Edwards JG, Shen Y-T, Kudej RK, Dietz R,
Leinwand LA, Nadal-Ginard B, Vatner SF: Identification of a
cis-acting regulatory element conferring inducibility of the
atrial natriuretic factor gene in acute pressure overload.
J
Clin Invest 1997; 100: 1294-1304
- Li P, Dietz R, von Harsdorf R: Reactive oxygen species induce
apoptosis of vascular smooth muscle cells. FEBS
lett 1997, 404: 249-252
- von Harsdorf R, Schott RJ, Shen YT, Vatner SF, Mahdavi V,
Nadal-Ginard B: Gene injection into canine myocardium as a useful
model for studying gene expression in the heart of large mammals.
Circ
Res 1993, 72: 688-695
- von Harsdorf R, Lang RE, Fullerton M, Woodcock EA: Myocardial
stretch stimulates phosphatidylinositol turnover. Circ
Res 1989, 65: 494-501
- von Harsdorf R, Lang RE, Fullerton M, Smith AI, Woodcock EA:
Right atrial dilatation increases inositol-(1,4,5)trisphosphate
accumulation. FEBS
lett 1988, 233: 201-205
Universitätsklinikum Charité - Medizinische Fakultät
der Humboldt-Universität zu Berlin, Campus Berlin-Buch
Franz-Volhard-Klinik,
Wiltbergstraße 50, D - 13125 Berlin - Tel.: +49 30
9417 2996 - Fax: +49 30 9497 074
Last Update: 20.06.2000 -
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