of the Max - MDC

Transcription Factors in
Myocardial Stress
Remodeling
PD M. W. Bergmann
(Helmholtz Fellow)
Cardiac hypertrophy represents the uniform response of the adult heart upon stress or damage. Downstream of
the large number of cytoplasmic signaling molecules a limited number of transcription factors integrate cardiac
hypertrophy signaling including CREB, NF-κB and β-catenin. As each of these factors has been shown to be required
for cardiac hypertrophy, the current question is which of the above mentioned transcription factors may be a suitable
target for pharmaceutical intervention preventing pathological cardiac remodeling resulting in heart failure,
while leaving adaptive pathways intact.
Projects:
The group has generated conditional transgenic mouse
models to study the role of transcription factors NF-κB and
β-catenin in adult cardiac remodeling. NF-κB inhibition
attenuated angiotensin II - mediated cardiomyocyte hypertrophy
in vivo. This discovery followed in vitro experiments,
which proposed a role of transcription factor NF-κB in cardiomyocyte
hypertrophy as well as protection against apoptosis.
The net effect on cardiac remodeling in vivo was
investigated by generating mice with cardiomyocyterestricted
expression of the NF-κB super-repressor IκBα∆N
(∆N MHC ) by use of the Cre/lox technique. ∆NMHC mice displayed
an attenuated hypertrophic response compared to
control mice upon infusion of angiotensin II (AngII) or isoproterenol
(Iso) by micro-osmotic pumps. Real-time RT-PCR
showed significantly reduced expression of hypertrophy
markers b-myosin heavy chain (MHC) and atrial natriuretic
peptide (ANP) in AngII-treated ∆N MHC mice. Neither cardiomyocyte
apoptosis nor left ventricular dilatation was
observed. Results from in vitro and in vivo experiments suggest
a role of NFκB in the regulation of prohypertrophic IL-6
receptor gp130 on mRNA and protein levels. The results
indicate that targeted inhibition of NFκB in cardiomyocytes
in vivo is sufficient to impair AngII- and Iso- induced hypertrophy
without increasing the susceptibility to apoptosis.
The project is carried out in close cooperation with Prof.
Claus Scheidereit heading the basic research group transcriptional
control at the MDC.
Recently, the group has applied the tools established in the
above mentioned project for investigating the role of β-
catenin in cardiac remodeling. β-catenin controls embryonic
heart development and therefore may ultimately allow to
understand the role of re-activation of embryonic development
pathways in the adult heart. Mice with heart restricted
gain and loss of β-catenin function have been generated by
inducible, heart restricted Cre recombinase expression. The
mice appeared normal at baseline with only moderate morphologic
and no functional abnormalities as detected by
echocardiography and immunohistochemistry. AngII infusion
induced cardiac hypertrophy both in wild-type mice
and in mice with β-catenin depletion. In contrast, mice with
stabilized β-catenin had decreased cross sectional area at
baseline and an abrogated hypertrophic response to AngII
infusion. Stabilizing β-catenin lead to impaired fractional
shortening compared to control littermates after AngII
stimulation. This functional deterioration was associated
with altered expression of T-box proteins Tbx5 and Tbx20 at
baseline and after AngII stimulation. In addition, atrophyrelated
protein IGFBP5 was upregulated in β-catenin stabilized
mice. These data suggest β-catenin down-regulation
to be required for adaptive cardiac hypertrophy preserving
LV-systolic function. Further studies are underway to clarify
the role of β-catenin modulation in endogenous regeneration
after infarct.
The above mentioned discoveries concerning specific signaling
pathways in cardiac remodeling have lead to the start of
a human trial on the in vivo effect of erythropoietin in
ischemic cardiac remodeling. Several studies suggest a beneficial
effect of erythropoietin on cardiac remodeling. An
investigator-initiated study has started at the Franz-Volhard
Clinic to assess the effect of a once-weekly EPO dose on cardiac
remodeling. The project is carried out in close cooperation
with Prof. Jens Jordan, MDC group “Center of Clinical
trials”.
36 Cardiovascular and Metabolic Disease Research