Wagner, Michael and Sadek, Mirna S. and Dybkova, Nataliya and Mason, Fleur E. and Klehr, Johann and Firneburg, Rebecca and Cachorro, Eleder and Richter, Kurt and Klapproth, Erik and Kuenzel, Stephan R. and Lorenz, Kristina and Heijman, Jordi and Dobrev, Dobromir and El-Armouche, Ali and Sossalla, Samuel and Kaemmerer, Susanne (2021) Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22 (9): 4816. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEART-FAILURE; CAMP; PHOSPHODIESTERASE-2; PHOSPHORYLATION; MITOCHONDRIA; ARRHYTHMIA; SODIUM; MODEL; LEAK; PDE2; arrhythmia; CaMKII; heart failure |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Sep 2022 04:20 |
| Last Modified: | 26 Sep 2022 04:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47939 |
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