Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jun 2

PMID 34062838

Citations 8

Authors

Michael Wagner

Mirna S Sadek

Nataliya Dybkova

Fleur E Mason

Johann Klehr

Rebecca Firneburg

Eleder Cachorro

Kurt Richter

Erik Klapproth

Stephan R Kuenzel

Kristina Lorenz

Jordi Heijman

Dobromir Dobrev

Ali El-Armouche

Samuel Sossalla

Susanne Kammerer

Affiliations

Soon will be listed here.

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 β-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 Ca-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 seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I and Ca-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 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.

Citing Articles

Cardiac cGMP Regulation and Therapeutic Applications.

Mishra S, Chander V, Kass D Hypertension. 2024; 82(2):185-196.

PMID: 39660453 PMC: 11732264. DOI: 10.1161/HYPERTENSIONAHA.124.21709.

Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.

Zaccolo M, Kovanich D Physiol Rev. 2024; 105(2):541-591.

PMID: 39115424 PMC: 7617275. DOI: 10.1152/physrev.00013.2024.

The role and mechanism of heme oxygenase-1 in arrhythmias.

Liu H, Zhang L, Yang F, Qian L, Wang R J Mol Med (Berl). 2024; 102(8):1001-1007.

PMID: 38937302 DOI: 10.1007/s00109-024-02462-4.

Abnormal phosphorylation / dephosphorylation and Ca dysfunction in heart failure.

Liu Y, Wang Q, Song Y, Song X, Fan Y, Kong L Heart Fail Rev. 2024; 29(4):751-768.

PMID: 38498262 DOI: 10.1007/s10741-024-10395-w.

Phosphodiesterase in heart and vessels: from physiology to diseases.

Fu Q, Wang Y, Yan C, Xiang Y Physiol Rev. 2023; 104(2):765-834.

PMID: 37971403 PMC: 11281825. DOI: 10.1152/physrev.00015.2023.

References

Landstrom A, Dobrev D, Wehrens X . Calcium Signaling and Cardiac Arrhythmias. Circ Res. 2017; 120(12):1969-1993. PMC: 5607780. DOI: 10.1161/CIRCRESAHA.117.310083. View

Cohn J, Goldstein S, GREENBERG B, Lorell B, Bourge R, Jaski B . A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med. 1998; 339(25):1810-6. DOI: 10.1056/NEJM199812173392503. View

Heijman J, Volders P, Westra R, Rudy Y . Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca(2+)-transient. J Mol Cell Cardiol. 2011; 50(5):863-71. PMC: 3075371. DOI: 10.1016/j.yjmcc.2011.02.007. View

Borner S, Schwede F, Schlipp A, Berisha F, Calebiro D, Lohse M . FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells. Nat Protoc. 2011; 6(4):427-38. DOI: 10.1038/nprot.2010.198. View

Weber S, Zeller M, Guan K, Wunder F, Wagner M, El-Armouche A . PDE2 at the crossway between cAMP and cGMP signalling in the heart. Cell Signal. 2017; 38:76-84. DOI: 10.1016/j.cellsig.2017.06.020. View

van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira A, Begieneman M, Bronzwaer J . Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012; 126(7):830-9. DOI: 10.1161/CIRCULATIONAHA.111.076075. View

Hua R, Adamczyk A, Robbins C, Ray G, Rose R . Distinct patterns of constitutive phosphodiesterase activity in mouse sinoatrial node and atrial myocardium. PLoS One. 2012; 7(10):e47652. PMC: 3471891. DOI: 10.1371/journal.pone.0047652. View

Enriquez A, Frankel D, Baranchuk A . Pathophysiology of ventricular tachyarrhythmias : From automaticity to reentry. Herzschrittmacherther Elektrophysiol. 2017; 28(2):149-156. DOI: 10.1007/s00399-017-0512-4. View

Acin-Perez R, Russwurm M, Gunnewig K, Gertz M, Zoidl G, Ramos L . A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J Biol Chem. 2011; 286(35):30423-30432. PMC: 3162402. DOI: 10.1074/jbc.M111.266379. View

10.

Glynn P, Musa H, Wu X, Unudurthi S, Little S, Qian L . Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo. Circulation. 2015; 132(7):567-77. PMC: 4543581. DOI: 10.1161/CIRCULATIONAHA.114.015218. View

11.

Shattock M, Ottolia M, Bers D, Blaustein M, Boguslavskyi A, Bossuyt J . Na+/Ca2+ exchange and Na+/K+-ATPase in the heart. J Physiol. 2015; 593(6):1361-82. PMC: 4376416. DOI: 10.1113/jphysiol.2014.282319. View

12.

Sag C, Mallwitz A, Wagner S, Hartmann N, Schotola H, Fischer T . Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner. J Mol Cell Cardiol. 2014; 76:94-105. DOI: 10.1016/j.yjmcc.2014.08.016. View

13.

Blanton R . cGMP Signaling and Modulation in Heart Failure. J Cardiovasc Pharmacol. 2019; 75(5):385-398. PMC: 7044023. DOI: 10.1097/FJC.0000000000000749. View

14.

Moreno J, Clancy C . Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol. 2011; 52(3):608-19. PMC: 3816394. DOI: 10.1016/j.yjmcc.2011.12.003. View

15.

Clerx M, Collins P, de Lange E, Volders P . Myokit: A simple interface to cardiac cellular electrophysiology. Prog Biophys Mol Biol. 2016; 120(1-3):100-14. DOI: 10.1016/j.pbiomolbio.2015.12.008. View

16.

Wagner S, Hacker E, Grandi E, Weber S, Dybkova N, Sossalla S . Ca/calmodulin kinase II differentially modulates potassium currents. Circ Arrhythm Electrophysiol. 2009; 2(3):285-94. PMC: 2734104. DOI: 10.1161/CIRCEP.108.842799. View

17.

Vandecasteele G, Hatem S, Verde I, Benardeau A, Mercadier J, Fischmeister R . cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. J Clin Invest. 1997; 99(11):2710-8. PMC: 508117. DOI: 10.1172/JCI119460. View

18.

Rosman G, Martins T, Sonnenburg W, Beavo J, Ferguson K, Loughney K . Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase. Gene. 1997; 191(1):89-95. DOI: 10.1016/s0378-1119(97)00046-2. View

19.

Baliga R, Preedy M, Dukinfield M, Chu S, Aubdool A, Bubb K . Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure. Proc Natl Acad Sci U S A. 2018; 115(31):E7428-E7437. PMC: 6077693. DOI: 10.1073/pnas.1800996115. View

20.

Kumari N, Gaur H, Bhargava A . Cardiac voltage gated calcium channels and their regulation by β-adrenergic signaling. Life Sci. 2017; 194:139-149. DOI: 10.1016/j.lfs.2017.12.033. View