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@ARTICLE{Bauer:143502,
author = {R. Bauer and H. Enns and A. Jungmann and B. Leuchs$^*$ and
C. Volz and S. Schinkel and W. J. Koch and P. W. Raake and
P. Most and H. A. Katus and O. J. Müller},
title = {{V}arious effects of {AAV}9-mediated β{ARK}ct gene therapy
on the heart in dystrophin-deficient (mdx) mice and
δ-sarcoglycan-deficient ({S}gcd-/-) mice.},
journal = {Neuromuscular disorders},
volume = {29},
number = {3},
issn = {0960-8966},
address = {Amsterdam [u.a.]},
publisher = {Elsevier Science},
reportid = {DKFZ-2019-01086},
pages = {231 - 241},
year = {2019},
abstract = {So far effective strategies to treat cardiomyopathy in
patients with muscular dystrophies are still not clearly
defined. Previously, treatment with β-blockers showed
beneficial effects on the development of cardiomyopathy in
dystrophin-deficient (mdx) mice, but not in
δ-sarcoglycan-deficient (Sgcd-/-) mice. We therefore aimed
to study a more specific approach to target maladaptive
β-adrenergic signalling in these mice. It has been shown
that lowering cardiac G-protein-coupled-receptor-kinase-2
(GRK2) activity with βARKct expression, a peptide inhibitor
of protein-coupled-receptor-kinase-2 (GRK2), results in
improvement of heart failure in several different animal
models. We therefore investigated whether adeno-associated
virus type 9 (AAV9)-mediated gene delivery of βARKct, could
ameliorate cardiac pathology in mdx and Sgcd-/- mice. We
found that long-term treatment with AAV9- βARKct-cDNA with
a cardiac-specific promoter significantly improves left
ventricular systolic function and reduces myocardial
hypertrophy in mdx mice, whereas only mild beneficial
effects on cardiac function is observed in Sgcd-/- mice.
Interestingly, in contrast to mdx mice neither GRK2 nor
nuclear-factor-kappaB (NFκB) were upregulated in Sgcd-/-
mice. Taken together, effectiveness of AAV-mediated βARKct
therapy may vary between different genetic mutations and
presumably depend on the state of adrenergic dysregulation
mediated through the upregulation of GRK2.},
cin = {F010},
ddc = {610},
cid = {I:(DE-He78)F010-20160331},
pnm = {316 - Infections and cancer (POF3-316)},
pid = {G:(DE-HGF)POF3-316},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30782477},
doi = {10.1016/j.nmd.2018.12.006},
url = {https://inrepo02.dkfz.de/record/143502},
}