(Hypertension. 1997;30:1348-1355.)
© 1997 American Heart Association, Inc.
Articles |
Regulation of the Rat Atrial Natriuretic Peptide Gene After Acute Imposition of Left Ventricular Pressure Overload
From the Medizinische Klinik und Poliklinik für Innere Medizin II, Universität Regensburg (T.C., S.R.H., G.A.J.R., H.S.); and the Institut für Pharmakologie und Toxikologie, Universität Münster, Germany (F.U.M.)
Abstract The upregulation of left ventricular
(LV) atrial natriuretic peptide (ANP) mRNA is a highly
conserved marker of cardiac hypertrophy. The aim of this
study was to further examine the pathway leading to ANP induction
during pressure overload of the heart. Systolic wall stress was
imposed acutely on isovolumetrically beating rat hearts in a
Langendorff apparatus (
=300x103
dyne/cm2). Northern and Western blots revealed that
elevated wall stress induced LV c-fos and
c-jun mRNAs (3.5- and 3-fold, P<.05
after 60 minutes), c-Fos and c-Jun proteins (3.9- and 4.3-fold,
P<.05 after 120 minutes), as well as ANP mRNA
(2.2-fold, P<.05 after 120 minutes). ANP upregulation
was prevented by inhibition of protein synthesis (cycloheximide).
Electrophoresis mobility shift assays were performed to link c-Fos and
c-Jun (ie, components of the heterodimeric transcription factor AP-1)
and ANP induction. A putative AP-1 binding site within the rat ANP
promoter (nucleotides -512 to -473) bound specifically to
nuclear proteins of wall stress–stimulated hearts. Antibodies directed
against c-Fos protein resulted in a shift of this DNA/protein complex,
suggesting physical interaction between AP-1 and the ANP promoter.
Myocardial transfection of promoter constructs revealed that after
acute imposition of wall stress, this AP-1 site enhanced a reporter
gene (8- to 10-fold compared with a minimal promoter,
P<.05). Interestingly, nuclear extracts of stimulated
hearts as well as pure AP-1 protein bound to a putative CRE site
(nucleotides -613 to -584) as well. Like the AP-1 site,
this cAMP-responsible element (CRE) site was found to enhance the
transfected ANP promoter/reporter gene significantly (17.5-fold,
P<.05). Mutation of either AP-1 or CRE sites did not
decrease reporter gene activity, whereas mutation of both resulted in
loss of inducibility. These experiments suggest that LV ANP regulation
after acute wall stress includes the activation of AP-1 and/or CRE
cis acting elements. However, the transient nature of
c-fos and c-jun upregulation also
suggests that AP-1 is not the only mediator of ANP induction in LV
hypertrophy.
Key Words: atrial natriuretic peptide • gene regulation • activator protein-1 • c-fos • gene transfection • heart
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