EN
Regulation of catecholamine-induced inotropy and arrhythmias by distinct PDE3- and PDE4-controlled cAMP microdomains in atrial fibrillation (RP2)
Principal Investigators
Project Summary and Goals
Both contractility and electrical stability are controlled by cAMP/PKA signaling in human atrium. In human atrial myocytes from patients in sinus rhythm, both phosphodiesterases PDE3 and PDE4 have been shown to control cAMP signaling. While PDE4 prevented arrhythmias evoked by β-adrenoceptor (β-AR) activation without affecting force, PDE3 reduced both the sensitivity for β-AR activation-evoked inotropy and arrhythmias. Interestingly, overexpression of PDE4B in the mouse heart reduced harmful effects of norepinephrine on ventricular tissue. It is unknown if the same holds true for human atrium. To answer this question, we will use human induced stem cell-derived cardiomyocytes (hiPSC-CM), a promising tool to study human heart electrophysiology and cAMP/PKA-dependent regulation. We have refined atrial-like hiPSC-CM a model to study human atrium physiology. Atrial engineered heart tissue (aEHT) recapitulates key finding of repolarization in human adult atrium. In close collaboration with Dr. Justus Stenzig and Dr. Arne Hansen (RP4), we will use aEHT-based tachypacing model of atrial fibrillation.
Aims Addressed by the Doctoral Candidates
- Study why inhibition of PDE3 and PDE4 may have different functional consequences.
- Investigate whether increasing hydrolytic activity of PDE4 may be an effective antiarrhythmic strategy.
Key Techniques
- Isolation of cardiomyocytes from human tissue
- Differentiation and culture of hiPSC-CM
- Förster resonance energy transfer (FRET) biosensors
- Generation of atrial EHT
- PKA-dependent phosphorylation status
- Recording of action potentials and ion currents
Publications
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Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation. Christ T, Rozmaritsa N, Engel A, Berk E, Knaut M, Metzner K, Canteras M, Ravens U, Kaumann A (2014). Proc Natl Acad Sci U S A. 111:11193-11198. -
Regulation of basal and norepinephrine-induced cAMP and ICa in hiPSC-cardiomyocytes: Effects of culture conditions and comparison to adult human atrial cardiomyocytes. Iqbal Z, Ismaili D, Dolce B, Petersen J, Reichenspurner H, Hansen A, Kirchhof P, Eschenhagen T, Nikolaev VO, Molina CE, Christ T (2021). Cell Signal. 82:109970. -
Cardiac overexpression of PDE4B blunts β-adrenergic response and maladaptive remodeling in heart failure. Karam S, Margaria JP, Bourcier A, Mika D, Varin A, Bedioune I, Lindner M, Bouadjel K, Dessillons M, Gaudin F, Lefebvre F, Mateo P, Lechène P, Gomez S, Domergue V, Robert P, Coquard C, Algalarrondo V, Samuel JL, Michel JB, Charpentier F, Ghigo A, Hirsch E, Fischmeister R, Leroy J, Vandecasteele G (2020). Circulation. 142:161-174. -
Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model. Mika D, Bobin P, Lindner M, Boet A, Hodzic A, Lefebvre F, Lechène P, Sadoune M, Samuel JL, Algalarrondo V, Rucker-Martin C, Lambert V, Fischmeister R, Vandecasteele G, Leroy J (2019). J Mol Cell Cardiol. 133:57-66. -
Human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium. Sönmez MI, Goldack S, Nurkkala E, Schulz C, Klampe B, Schulze T, Hansen A, Eschenhagen T, Koivumäki J, Christ T (2024). Europace. 26:140.