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Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice

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-/...

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Main Authors: Bauer, Ralf (Author) , Enns, Helene (Author) , Jungmann, Andreas (Author) , Volz, Hans Christian (Author) , Schinkel, Stefanie (Author) , Raake, Philip (Author) , Most, Patrick (Author) , Katus, Hugo (Author) , Müller, Oliver J. (Author)
Format: Article (Journal)
Language:English
Published: 2019
In: Neuromuscular disorders
Year: 2019, Volume: 29, Issue: 3, Pages: 231-241
ISSN:1873-2364
DOI:10.1016/j.nmd.2018.12.006
Online Access:Verlag, Volltext: http://dx.doi.org/10.1016/j.nmd.2018.12.006
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Author Notes:Ralf Bauer, Helene Enns, Andreas Jungmann, Barbara Leuchs, Christian Volz, Stefanie Schinkel, Walter J. Koch, Philip W. Raake, Patrick Most, Hugo A. Katus, Oliver J. Müller
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Summary: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.
Item Description:Gesehen am 13.06.2019
Physical Description:Online Resource
ISSN:1873-2364
DOI:10.1016/j.nmd.2018.12.006

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