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Expression of nuclear-acting early-response genes in the rat heart : implications for cardiac hypertrophy


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Hannan, R 1994 , 'Expression of nuclear-acting early-response genes in the rat heart : implications for cardiac hypertrophy', PhD thesis, University of Tasmania.

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Post-natal growth of the mammalian heart is characterized by an increase in size of pre-existing
cardiomyocytes (hypertrophy) rather than an increase in their number (hyperplasia). The primary stimuli
for this growth process are not clearly understood but seem to involve both hemodynamic and hormonal
factors. A major challenge to researchers has been to clearly define the signals that activate and regulate
cardiac hypertrophy and to elucidate the intracellular transducing mechanisms which couple the
hypertrophic stimuli to the long term changes in cardiac phenotype and function. Of the most likely
candidate molecular signals the nuclear-acting early-response genes are of particular interest since their
protein products are thought to play key roles in linking extracellular signals with terminal patterns of
gene expression during growth and differentiation. The work in this thesis has examined the ability of
various hypertrophic stimuli to modulate the expression of nuclear acting early response genes in the rat
heart both in vivo and in vitro. A single injection of norepinephrine (2.5 ug/kg to 2.5 mg/kg) transiently
increased mRNA levels of the nuclear acting early-response genes c-myc, c-fos, c-jun, fra-1 and fra-2 in
the rat heart. Similar responses were also observed following chronic infusion of norepinephrine (100
ug/kg/h) but not in response to treatment with the hypertrophic hormone triiodo-L-thyroxine.
Hybridization histochemistry and immunocytochemistry techniques were used to localize early response
genes to particular cell types and regions of the heart. Following norepinephrine administration (2.5
mg/kg) Fos protein transiently accumulated in the cardiac myocytes and to a much lesser extent other cell
types. In direct contrast, little Myc immunostaining was observed in the cardiac myocytes with greatest
expression being localized to the cardiac non-myocyte population, presumably fibroblasts and cells of
the vasculature system. The observed responses for both genes was not uniform but appeared greatest in
the left atrium and left ventricle with lesser expression elsewhere. In order to differentiate the complex
systemic interactions of norepinephrine from its direct actions upon the heart an isolated perfused heart
system was employed. Both elevated perfusion pressure (60-120 mmHg) and the inclusion of
norepinephrine (1 nM to 1 uM) in the perfusion buffer (60 mmHg) led to elevated mRNA levels of
c-myc , c-fos, fra-1 and fra-2. These findings demonstrate the utitlity of the isolated perfused heart system
as a model to study separately the effects of pressure load and NE on gene expression during the early
stages of cardiac hypertrophy. Taken together with the in vivo results they lend further support to the
notion that the products of early-response genes structurally or functionally related to c-fos may mediate
the hypertrophic actions of norepinephrine and pressure overload. In contrast, c-myc expression may be
associated with the proliferation of cardiac non-myocyte cells which occurs concomitant with cardiac

Item Type: Thesis - PhD
Authors/Creators:Hannan, R
Keywords: Heart, Genetic regulation, Cellular control mechanisms
Copyright Holders: The Author
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Copyright 1994 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
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Thesis (Ph.D.)--University of Tasmania, 1994

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