TY  - JOUR
A1  - Shemer, Yuval
A1  - Mekies, Lucy N.
A1  - Ben Jehuda, Ronen
A1  - Baskin, Polina
A1  - Shulman, Rita
A1  - Eisen, Binyamin
A1  - Regev, Danielle
A1  - Arbustini, Eloisa
A1  - Gerull, Brenda
A1  - Gherghiceanu, Mihaela
A1  - Gottlieb, Eyal
A1  - Arad, Michael
A1  - Binah, Ofer
T1  - Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes
JF  - International Journal of Molecular Sciences
N2  - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
KW  - LMNA
KW  - dilated cardiomyopathy
KW  - iPSC-CMs
KW  - electrophysiology
KW  - arrhythmia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285673
SN  - 1422-0067
VL  - 22
IS  - 15
ER  - 
TY  - JOUR
A1  - Wagner, Michael
A1  - Sadek, Mirna S.
A1  - Dybkova, Nataliya
A1  - Mason, Fleur E.
A1  - Klehr, Johann
A1  - Firneburg, Rebecca
A1  - Cachorro, Eleder
A1  - Richter, Kurt
A1  - Klapproth, Erik
A1  - Kuenzel, Stephan R.
A1  - Lorenz, Kristina
A1  - Heijman, Jordi
A1  - Dobrev, Dobromir
A1  - El-Armouche, Ali
A1  - Sossalla, Samuel
A1  - Kämmerer, Susanne
T1  - Cellular mechanisms of the anti-arrhythmic effect of cardiac PDE2 overexpression
JF  - International Journal of Molecular Sciences
N2  - 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\(^{2+}\)-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 Ca\(^{2+}\)-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.
KW  - PDE2
KW  - arrhythmia
KW  - CaMKII
KW  - heart failure
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285888
SN  - 1422-0067
VL  - 22
IS  - 9
ER  -