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@ARTICLE{Kant:861126,
author = {Kant, Sebastian and Freytag, Benjamin and Herzog, Antonia
and Reich, Anna and Merkel, Rudolf and Hoffmann, Bernd and
Krusche, Claudia A. and Leube, Rudolf E.},
title = {{D}esmoglein 2 mutation provokes skeletal muscle actin
expression and accumulation at intercalated discs in murine
hearts},
journal = {Journal of cell science},
volume = {132},
number = {5},
issn = {1477-9137},
address = {Cambridge},
publisher = {Company of Biologists Limited},
reportid = {FZJ-2019-01683},
pages = {jcs199612 -},
year = {2019},
abstract = {Arrhythmogenic cardiomyopathy (AC) is an incurable
progressive disease that is linked to mutations in genes
coding for components of desmosomal adhesions that are
localized to the intercalated disc region, which
electromechanically couples adjacent cardiomyocytes. To
date, the underlying molecular dysfunctions are not well
characterized. In two murine AC models, we find an
upregulation of the skeletal muscle actin gene (Acta1),
which is known to be a compensatory reaction to compromised
heart function. Expression of this gene is elevated prior to
visible morphological alterations and clinical symptoms, and
persists throughout pathogenesis with an additional major
rise during the chronic disease stage. We provide evidence
that the increased Acta1 transcription is initiated through
nuclear activation of the serum response transcription
factor (SRF) by its transcriptional co-activator
megakaryoblastic leukemia 1 protein (MKL1, also known as
MRTFA). Our data further suggest that perturbed desmosomal
adhesion causes Acta1 overexpression during the early stages
of the disease, which is amplified by transforming growth
factor β (TGFβ) release from fibrotic lesions and
surrounding cardiomyocytes during later disease stages.
These observations highlight a hitherto unknown molecular AC
pathomechanism.},
cin = {ICS-7},
ddc = {570},
cid = {I:(DE-Juel1)ICS-7-20110106},
pnm = {552 - Engineering Cell Function (POF3-552)},
pid = {G:(DE-HGF)POF3-552},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30659114},
UT = {WOS:000461414300006},
doi = {10.1242/jcs.199612},
url = {https://juser.fz-juelich.de/record/861126},
}