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148 Hypertonie 2011 - Poster Hypertonie 2011 - Poster 149
assay in gonadal adipose tissue(AT).
Male mice exhibited accelerated BW gain,
while females gained BW more slowly but
constantly (BW gain; m134.6±1.7%, f79.2±3.7%;
p< 0.001). In consonance the weight gain
efficiency (weight gain[g]/[g]food intake) was
significantly lower in females and they showed
a significantly higher lean mass-specific EE
compared to males (p< 0.001). In both sexes
reduction of BW was mainly mediated by a loss
of AT. Interestingly, relative loss of gonadal AT
was higher in females. In this phase females
showed higher rates of forskolin-stimulated
lipolysis in the AT, a lower respiratory quotient
(m0.87±0.02, f0.84±0.02; p< 0.01) and increased
levels of free glycerol in the serum supporting
the hypothesis of enhanced lipolysis and lipid
oxidation in females during BW loss. Analysis
of AT lipolysis in ERα knock out mice indicated
that sex-dependent regulation of lipolysis
seems to depend on the presence of ERα in AT.
In consonance ERα overexpression in 3T3-L1
cells resulted in an induction of ATGL(adipose
triglyceride lipase) expression.
The study shows a sex-specific regulation of
BW reduction. Sexual dimorphisms likely
involve ERα-dependent regulation of AT metabolism
such as lipolysis providing a potential
therapeutic target for the maintenance of
reduced body weight.
Herz und hypertensive
Herzkrankheit
PS 13
Obesity and Metabolic Syndrome in
Hypertension Accelerate Diastolic
Dysfunction
Linz D. 1 , Hohl M. 1 , Mahfoud F. 1 , Reil J.-C. 1 ,
Hübschle T. 2 , Linz W. 2 , Böhm M. 1
1Uniklinikum des Saarlandes, Homburg,
Germany, 2Sanofi-Aventis GmbH, Frankfurt,
Germany
Background: Hypertension and obesity are
associated with diastolic left ventricular (LV)
dysfunction which is characterized by increased
interstitial fibrosis and changes in calcium
handling, impairing compliance and relaxation.
We investigated the effect of genetic obesity
and metabolic syndrome on development of
diastolic dysfunction in a hypertensive rat model
with a mutation in the leptin receptor (SHR-ob)
compared to spontaneously hypertensive rats
(SHR) and normotensive controls (SD).
Method: LV function was investigated by cardiac
MRI- and invasive LV-pressure measurements.
LV-interstitial fibrosis was quantified by Sirius
red staining and by Real-Time PCR quantification
of fibrosis-related gene expression (TGFbeta
and Col1a). Phosphorylation status of
phospholamban (PLB) as well as Serca2a protein
expression was determined by immunoblotting.
Results: At the age of 38 weeks, blood pressure
did not differ in SHR-ob compared to SHR (252±7
vs. 241.24±7mmHg, ns) but was increased
compared to SD (155±2mmHg, p< 0.0001).
SHR-ob showed a significant increase in body
weight, compared to SD and SHR (638.3±14.6
vs. 400.7±7.3 and 465.5±17.4g; p< 0.001,
respectively) and a pathological glucose tolerance.
In SHR-ob LV ejection fraction was moderately
impaired compared to SHR and SD (46.2±1.1 vs.
54.4±3.9 and 59.6±1.85%, p< 0.01 for both). LV
end-diastolic pressure and relaxation constant
tau were more increased in SHR-ob than
in SHR (21.5±4.1 vs. 5.9±0.81mmHg,
p< 0.001 and 18.6±1.6 vs. 12.7±1.1ms;
p< 0.01, respectively) when compared
to SD (4.3±1.1mmHg and 8.8±0.62ms, respectively,
p< 0.01 for all). LV tissue fibrosis, Col1aand
TGFbeta gene expression were increased
in SHR-ob compared to SHR and SD.
LV-Serca2a protein levels and PLB-phosphorylation
were not significantly modified.
Conclusions: At similar blood pressure levels,
obesity and metabolic syndrome accelerate
diastolic dysfunction in SHR-ob by a pronounced
increase in LV-fibrosis involving TGF-beta and
Col1a expression and not by changes in Serca2a
protein levels or PLB-phosporylation.
PS 14
Genome-wide Fetal Expression Profiling in
a Genetic Model of Hypertension Supports a
Fetal Genetic Predisposition to Hypertensive
Left Ventricular Hypertrophy
Grabowski K. 1 , Schulte L. 1 , Witten A. 2 , Schulz
A. 1 , Stoll M. 2 , Kreutz R. 1
1Charite Universitätsmedizin Berlin, Klinische
Pharmakologie und Toxikologie, Berlin,
Germany, 2Universität Münster, Leibniz-Institut
für Arterioskleroseforschung, Münster, Germany
Research question: Reactivation of fetal gene
expression patterns has been demonstrated to
play a crucial role in common cardiac diseases
in adult life including left ventricular hyper-
trophy (LVH). Thus, increased wall stress and
neurohumoral activation are discussed to induce
the return to expression of fetal genes after
birth in LVH. We therefore aimed to test whether
fetal gene expression programs are linked to the
genetic predisposition to LVH. We performed
genome-wide fetal gene expression analysis in
a genetic rat model of LVH, i.e. the stroke-prone
spontaneously hypertensive rat (SHRSP). In previous
work we could demonstrate the impact of
a quantitative trait locus (QTL) on rat chromosome
1 (RNO1) for LVH in SHRSP. This QTL was
mapped in comparison to the Fischer (F344) rat
representing a contrasting inbred rat model with
a low left ventricular mass index.
Methods: Genome-wide gene expression analysis
was performed by microarray-technology.
We extracted RNA from heart tissue of F344,
SHRSP and consomic SHRSP-1F344 rats (n=6,
respectively) at day 20 of development (E20). We
compared all three groups to indentify differentially
expressed genes and specifically tested the
role of RNO1. Statistical analysis was performed
by using the Illumina custom error model.
Results: We identified overall more than 100
genes with differential expression among the
three strains. From six genes located on RNO1,
one gene was located within the LVH QTL, i.e.
Eif3s8 (eukaryotic translation initiation factor
3, subunit C). Eif3s8 was higher expressed in
consomic SHRSP-1F344 than in SHRSP. In
contrast another gene on RNO1 stearoyl-CoA
desaturase showed lower expression in
SHRSP-1F344 than in SHRSP.
Conclusion: Our analysis of fetal gene expression
patterns in rats with genetic hypertension
identified new candidate genes for LVH. The
candidates with differential fetal expression
provide a basis for further analyses to test a
genetic predisposition for LVH with fetal origin.