Journal Article

DKFZ-2019-01086

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice.

Bauer, R. ; Enns, H. ; Jungmann, A. ; Leuchs, B.DKFZ* ; Volz, C. ; Schinkel, S. ; Koch, W. J. ; Raake, P. W. ; Most, P. ; Katus, H. A. ; Müller, O. J.

2019
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.nmd.2018.12.006

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.

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Contributing Institute(s):

1. Tumorvirologie (F010)

Research Program(s):

1. 316 - Infections and cancer (POF3-316) (POF3-316)

Appears in the scientific report 2019

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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