Abstract
Cardiac hypertrophy is an adaptive response of the heart to a variety of
mechanical, hemodynamic, neurohumoral, and pathologic stimuli. Prolonged
pathophysiological load leads to development of left ventricular hypertrophy and
ultimately to heart failure. The natriuretic peptides including the B-type
natriuretic peptide (BNP) provide the physiological feedback mechanism to
suppress the load signal. The aim of the present study was to evaluate the
cis elements within the BNP promoter that mediate the
cardiac
load responses in vivo, and to study the involvement of
paracrine factors, such as endothelin-1 (ET-1) and angiotensin II (Ang II) in
activating these transcription factors.
In this study, cardiac overload was produced by bilateral nephrectomy, and
infusions of arginine8-vasopressin (AVP) or Ang II. In
isolated perfused rat heart, the direct wall stretch was achieved by inflating
the left ventricular balloon. To identify the cis elements
within the BNP promoter that mediate hemodynamic overload response, the approach
of DNA injection into the myocardium was used. Mutation or deletion of proximal
BNP GATA sites abrogated the response to nephrectomy. AVP-induced acute pressure
overload increased left ventricular BNP mRNA and peptide levels. In gel mobility
shift assays, pressure overload produced rapid activation of transcription factor
GATA4 DNA binding, which was completely inhibited by the ET-1 receptor antagonist
bosentan. Both ET-1 and Ang II receptor antagonism inhibited the wall
stretch-induced increases in left ventricular GATA4 and AP-1 binding activities
in isolated perfused heart preparation. BNP promoter activity and BNP mRNA and
peptide levels were regulated distinctly in chronic hemodynamic overload produced
by Ang II.
In conclusion, GATA4 appears to be necessary and sufficient to confer
transcriptional activation of BNP gene during hemodynamic stress in
vivo. ET-1 is a signaling molecule mediating the cardiac response to
acute pressure overload in vivo. In isolated rat heart, Ang
II and ET-1 are required for the stimulation of GATA4 and AP-1 binding activity
in response to direct left ventricular wall stretch. Finally, posttranscriptional
mechanisms play an important role in the regulation of BNP gene expression in
pressure overload produced by Ang II in vivo.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-6532-7 |
| Date | 24 October 2001 |
| Creators | Hautala, N. (Nina) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2001 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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