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Cyclic mechanical strain causes cAMP-response element binding protein activation by different pathways in cardiac fibroblasts

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Published Online: Jul 31st 2018 Heart International 2010;5(1):e3 DOI: https://doi.org/10.4081/hi.2010.e3
Authors: Britta Husse, Gerrit Isenberg
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Abstract:
Overview

The transcription factor cAMP-response element
binding protein (CREB) mediates the
mechanical strain-induced gene expression in
the heart. This study investigated which signaling
pathways are involved in the straininduced
CREB activation using cultured ventricular
fibroblasts from adult rat hearts. CREB
phosphorylation was analyzed by immunocytochemistry
and ELISA. Cyclic mechanical strain
(1 Hz and 5% elongation) for 15 min induced
CREB phosphorylation in all CREB-positive
fibroblasts. Several signaling transduction
pathways can contribute to strain-induced
CREB activation. The inhibition of PKA, PKC,
MEK, p38-MAPK or PI3-kinase partially
reduced the strain-induced CREB phosphorylation.
Activation of PKA by forskolin or PKC by
PMA resulted in a level of CREB phosphorylation
comparable to the reduced level of the
strain-induced CREB phosphorylation in the
presence of PKA or PKC inhibitors. Signaling pathways involving PKC, MEK, p38-MAPK or
PI3-kinase seem to converge during straininduced
CREB activation. PKA interacted additively
with the investigated signaling pathways.
The strain-induced c-Fos expression can
be reduced by PKC inhibition but not by PKA
inhibition. Our results suggest that the complete
strain-induced CREB phosphorylation
involves several signaling pathways that have
a synergistic effect. The influence on gene
expression is dependent on the level and the
time of CREB stimulation. These wide-ranging
possibilities of CREB activation provide a
graduated control system.

Keywords

Strain, mechanotransduction, cAMP response element binding protein, c-Fos, fibroblasts.

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Correspondence

Britta Husse, Department of Physiology, Martin-Luther-University Halle/ Wittenberg, Magdeburger Street 6, D 06097 Halle, Germany. E-mail: britta.husse@medizin.uni-halle.de

Received

2009-07-05

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