@article{9b943f1229ef4f839359b34f2b3255c4,
title = "Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression",
abstract = "Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to beta-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I-CaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I-NaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.",
keywords = "ARRHYTHMIA, CAMP, CaMKII, HEART-FAILURE, LEAK, MITOCHONDRIA, MODEL, PDE2, PHOSPHODIESTERASE-2, PHOSPHORYLATION, SODIUM, arrhythmia, heart failure",
author = "Michael Wagner and Sadek, {Mirna S.} and Nataliya Dybkova and Mason, {Fleur E.} and Johann Klehr and Rebecca Firneburg and Eleder Cachorro and Kurt Richter and Erik Klapproth and Kuenzel, {Stephan R.} and Kristina Lorenz and Jordi Heijman and Dobromir Dobrev and Ali El-Armouche and Samuel Sossalla and Susanne Kaemmerer",
note = "Funding Information: Acknowledgments: We wish to thank Romy Kempe for cell isolation, Annett Opitz and Mario G{\"u}nscht for handling and genotyping of mice, Stefano Gaburro, Kim Hansing, Timo Schulte, Andreas Schwab, Issam Abu-Taha, and Manja Newe for their technical support. We acknowledge support by the Open Access Publication Funds of the SLUB/TU Dresden. Funding Information: Funding: This work was supported by the German Research Foundation (DFG) grants EL 270/7-3, Transregio-SFB CRC/TRR 205 to A.E.-A., grant KA 4194/3-3 to S.K., project no. 288034826 of international research training group (IRTG) 2251 to A.E.-A. and S.K., grant WA 2586/4-1 to M.W., SFB1116 grant to K.L. and by research stipend of the German Heart Foundation/German Foundation of Heart Research F/45/19 to S.K., F/34/19 to E.K. and K/10/20 to J.K. J.H. is supported by the Netherlands Organization for Scientific Research NWO/ZonMW Vidi 09150171910029. D.D. is supported by grants from National Institutes of Health (R01HL136389, R01HL131517 and R01HL089598), the DFG (Do 769/4-1), and the European Union (large-scale integrative project MEASTRIA, No. 965286 to D.D.). S.S. is funded by the German Foundation of Heart Research F/40/18. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = may,
doi = "10.3390/ijms22094816",
language = "English",
volume = "22",
journal = "International journal of molecular sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "9",
}