Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression.
Action Potentials
/ drug effects
Animals
Anti-Arrhythmia Agents
/ pharmacology
Arrhythmias, Cardiac
/ chemically induced
Calcium
/ metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/ genetics
Cyclic AMP
/ genetics
Cyclic GMP
/ genetics
Cyclic Nucleotide Phosphodiesterases, Type 2
/ genetics
Gene Expression Regulation
/ genetics
Guanine Nucleotide Exchange Factors
/ genetics
Heart
/ physiopathology
Humans
Isoproterenol
/ toxicity
Mice
Myocytes, Cardiac
/ drug effects
CaMKII
PDE2
arrhythmia
heart failure
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
01 May 2021
01 May 2021
Historique:
received:
31
03
2021
revised:
27
04
2021
accepted:
28
04
2021
entrez:
2
6
2021
pubmed:
3
6
2021
medline:
29
6
2021
Statut:
epublish
Résumé
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. Cellular arrhythmia, ion currents, and Ca 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 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.
Sections du résumé
BACKGROUND
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
METHODS
Cellular arrhythmia, ion currents, and Ca
RESULTS
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
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 34062838
pii: ijms22094816
doi: 10.3390/ijms22094816
pmc: PMC8125727
pii:
doi:
Substances chimiques
Anti-Arrhythmia Agents
0
Epac protein, mouse
0
Guanine Nucleotide Exchange Factors
0
Cyclic AMP
E0399OZS9N
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
Cyclic Nucleotide Phosphodiesterases, Type 2
EC 3.1.4.17
Cyclic GMP
H2D2X058MU
Isoproterenol
L628TT009W
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : German Research Foundation
ID : EL 270/7-3
Organisme : German Research Foundation
ID : Transregio-SFB CRC/TRR 205
Organisme : German Research Foundation
ID : KA 4194/3-3
Organisme : German Research Foundation
ID : project no. 288034826 - international research training group (IRTG) 2251
Organisme : German Research Foundation
ID : WA 2586/4-1
Organisme : German Research Foundation
ID : SFB1116
Organisme : German heart Foundation/German Foundation of Heart Research
ID : F/45/19
Organisme : German heart Foundation/German Foundation of Heart Research
ID : F/34/19
Organisme : German Foundation of Heart Research
ID : K/10/20
Organisme : German Foundation of Heart Research
ID : F/40/18
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