%0 Journal Article
%A Bauer, Ralf
%A Enns, Helene
%A Jungmann, Andreas
%A Leuchs, Barbara
%A Volz, Christian
%A Schinkel, Stefanie
%A Koch, Walter J
%A Raake, Philip W
%A Most, Patrick
%A Katus, Hugo A
%A Müller, Oliver J
%T Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice.
%J Neuromuscular disorders
%V 29
%N 3
%@ 0960-8966
%C Amsterdam [u.a.]
%I Elsevier Science
%M DKFZ-2019-01086
%P 231 - 241
%D 2019
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30782477
%R 10.1016/j.nmd.2018.12.006
%U https://inrepo02.dkfz.de/record/143502