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

• Verfasst von: Bauer, Ralf [VerfasserIn]
• Verfasst von: Enns, Helene [VerfasserIn]
• Verfasst von: Jungmann, Andreas [VerfasserIn]
• Verfasst von: Volz, Hans Christian [VerfasserIn]
• Verfasst von: Schinkel, Stefanie [VerfasserIn]
• Verfasst von: Raake, Philip [VerfasserIn]
• Verfasst von: Most, Patrick [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Müller, Oliver J. [VerfasserIn]
• Titel: Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice
• Verf.angabe: 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
• Jahr: 2019
• Umfang: 11 S.
• Fussnoten: Gesehen am 13.06.2019
• Titel Quelle: Enthalten in: Neuromuscular disorders
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1991
• Jahr Quelle: 2019
• Band/Heft Quelle: 29(2019), 3, Seite 231-241
• ISSN Quelle: 1873-2364
• DOI: doi:10.1016/j.nmd.2018.12.006
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cardiomyopathy
• Sach-SW: Gene therapy
• Sach-SW: muscular dystrophy
• Sach-SW: β-adrenergic signalling
• K10plus-PPN: 1667349481

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.