Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation.

Autor:	Pavlaki N; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany., Froese A; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany., Li W; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., De Jong KA; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany., Geertz B; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany.; Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany., Subramanian H; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany., Mohagaonkar S; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany., Luo X; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., Schubert M; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., Wiegmann R; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany.; Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Margaria JP; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.; Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, Università Vita-Salute San Raffaele, Milan, Italy., Ghigo A; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy., Kämmerer S; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., Hirsch E; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy., El-Armouche A; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., Guan K; Institute of Pharmacology and Toxicology, Technical University of Dresden, Dresden, Germany., Nikolaev VO; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Martinistr. 52, D-20246 Hamburg, Germany.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Jul 31; Vol. 120 (9), pp. 1011-1023.
DOI:	10.1093/cvr/cvae094
Abstrakt:	Aims: Gene therapy with cardiac phosphodiesterases (PDEs), such as phosphodiesterase 4B (PDE4B), has recently been described to effectively prevent heart failure (HF) in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here, we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload-induced HF in mice by acting on and restoring altered cAMP compartmentation in distinct subcellular microdomains. Methods and Results: HF was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3, or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis, and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentation in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts, and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human-induced pluripotent stem-derived cardiomyocytes with the A2254V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. Conclusion: Our data indicate that gene therapy with phosphodiesterases can prevent HF including associated cardiac remodelling and arrhythmias by restoring altered cAMP compartmentation in functionally relevant subcellular microdomains. Competing Interests: Conflict of interest: A.G. and E.H. are cofounders and shareholders of Kither Biotech, a pharmaceutical company developing PI3K inhibitors for respiratory diseases, not in conflict with the content of this manuscript. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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