PMID- 30782477
OWN - NLM
STAT- MEDLINE
DCOM- 20200601
LR  - 20200601
IS  - 1873-2364 (Electronic)
IS  - 0960-8966 (Linking)
VI  - 29
IP  - 3
DP  - 2019 Mar
TI  - Various effects of AAV9-mediated betaARKct gene therapy on the heart in 
      dystrophin-deficient (mdx) mice and delta-sarcoglycan-deficient (Sgcd-/-) mice.
PG  - 231-241
LID - S0960-8966(18)30150-0 [pii]
LID - 10.1016/j.nmd.2018.12.006 [doi]
AB  - So far effective strategies to treat cardiomyopathy in patients with muscular 
      dystrophies are still not clearly defined. Previously, treatment with beta-blockers 
      showed beneficial effects on the development of cardiomyopathy in 
      dystrophin-deficient (mdx) mice, but not in delta-sarcoglycan-deficient (Sgcd-/-) 
      mice. We therefore aimed to study a more specific approach to target maladaptive 
      beta-adrenergic signalling in these mice. It has been shown that lowering cardiac 
      G-protein-coupled-receptor-kinase-2 (GRK2) activity with betaARKct 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 betaARKct, could ameliorate cardiac pathology in mdx and Sgcd-/- mice. We found 
      that long-term treatment with AAV9- betaARKct-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 (NFkappaB) were upregulated in Sgcd-/- mice. Taken 
      together, effectiveness of AAV-mediated betaARKct therapy may vary between different 
      genetic mutations and presumably depend on the state of adrenergic dysregulation 
      mediated through the upregulation of GRK2.
CI  - Copyright (c) 2018. Published by Elsevier B.V.
FAU - Bauer, Ralf
AU  - Bauer R
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany. Electronic address: ralf.bauer@wiesloch-zwei.de.
FAU - Enns, Helene
AU  - Enns H
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany.
FAU - Jungmann, Andreas
AU  - Jungmann A
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany.
FAU - Leuchs, Barbara
AU  - Leuchs B
AD  - Tumor Virology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 
      Heidelberg, Germany.
FAU - Volz, Christian
AU  - Volz C
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany.
FAU - Schinkel, Stefanie
AU  - Schinkel S
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany.
FAU - Koch, Walter J
AU  - Koch WJ
AD  - Center for Translational Medicine, Temple University School of Medicine, 3500 N 
      Broad St, 19140 Philadelphia, PA, USA.
FAU - Raake, Philip W
AU  - Raake PW
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), 
      Partner Site Heidelberg/Mannheim, Germany.
FAU - Most, Patrick
AU  - Most P
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), 
      Partner Site Heidelberg/Mannheim, Germany; Center for Molecular and Translational 
      Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 
      Heidelberg, Germany.
FAU - Katus, Hugo A
AU  - Katus HA
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), 
      Partner Site Heidelberg/Mannheim, Germany.
FAU - Muller, Oliver J
AU  - Muller OJ
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120 Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), 
      Partner Site Heidelberg/Mannheim, Germany; Department of Internal Medicine III, 
      University of Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181220
PL  - England
TA  - Neuromuscul Disord
JT  - Neuromuscular disorders : NMD
JID - 9111470
RN  - 0 (Dystrophin)
RN  - 0 (Sarcoglycans)
RN  - 0 (Sgcd protein, mouse)
SB  - IM
MH  - Animals
MH  - Cardiomyopathies/*genetics
MH  - *Dependovirus/genetics
MH  - Dystrophin/*deficiency/genetics
MH  - Genetic Therapy/methods
MH  - Heart/physiopathology
MH  - Heart Failure/genetics/physiopathology
MH  - Mice, Inbred mdx
MH  - Mice, Transgenic
MH  - Muscular Dystrophies/*genetics/metabolism
MH  - Sarcoglycans/*genetics
MH  - Ventricular Function, Left/genetics
OTO - NOTNLM
OT  - Gene therapy
OT  - cardiomyopathy
OT  - muscular dystrophy
OT  - beta-adrenergic signalling
EDAT- 2019/02/21 06:00
MHDA- 2020/06/02 06:00
CRDT- 2019/02/21 06:00
PHST- 2018/02/25 00:00 [received]
PHST- 2018/10/21 00:00 [revised]
PHST- 2018/12/16 00:00 [accepted]
PHST- 2019/02/21 06:00 [pubmed]
PHST- 2020/06/02 06:00 [medline]
PHST- 2019/02/21 06:00 [entrez]
AID - S0960-8966(18)30150-0 [pii]
AID - 10.1016/j.nmd.2018.12.006 [doi]
PST - ppublish
SO  - Neuromuscul Disord. 2019 Mar;29(3):231-241. doi: 10.1016/j.nmd.2018.12.006. Epub 
      2018 Dec 20.