1. Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation.
- Author
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Pavlaki N, Froese A, Li W, De Jong KA, Geertz B, Subramanian H, Mohagaonkar S, Luo X, Schubert M, Wiegmann R, Margaria JP, Ghigo A, Kämmerer S, Hirsch E, El-Armouche A, Guan K, and Nikolaev VO
- Subjects
- Animals, Humans, Mice, Inbred C57BL, Male, Arrhythmias, Cardiac enzymology, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Arrhythmias, Cardiac prevention & control, Ventricular Remodeling, Induced Pluripotent Stem Cells enzymology, Induced Pluripotent Stem Cells metabolism, Second Messenger Systems drug effects, Ventricular Function, Left, Calcium Signaling, Phosphorylation, Heart Rate, Cyclic AMP metabolism, Heart Failure enzymology, Heart Failure genetics, Heart Failure therapy, Heart Failure physiopathology, Heart Failure metabolism, Genetic Therapy, Cyclic Nucleotide Phosphodiesterases, Type 2 metabolism, Cyclic Nucleotide Phosphodiesterases, Type 2 genetics, Myocytes, Cardiac enzymology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Disease Models, Animal, Ryanodine Receptor Calcium Release Channel metabolism, Ryanodine Receptor Calcium Release Channel genetics
- Abstract
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.)
- Published
- 2024
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