TY  - JOUR
AU  - Bauer, Ralf
AU  - Enns, Helene
AU  - Jungmann, Andreas
AU  - Leuchs, Barbara
AU  - Volz, Christian
AU  - Schinkel, Stefanie
AU  - Koch, Walter J
AU  - Raake, Philip W
AU  - Most, Patrick
AU  - Katus, Hugo A
AU  - Müller, Oliver J
TI  - Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice.
JO  - Neuromuscular disorders
VL  - 29
IS  - 3
SN  - 0960-8966
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2019-01086
SP  - 231 - 241
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30782477
DO  - DOI:10.1016/j.nmd.2018.12.006
UR  - https://inrepo02.dkfz.de/record/143502
ER  -