Journal Article Ahead of print
PubMed: 41731308 DOI: 10.1111/bph.70380
Higher sensitivity to ouabain-induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes than human adult heart tissue despite similar Na +/K +-ATPase pump current amplitudes.
Br J Pharmacol
Authors: Djemail Ismaili, Paavo Virtanen, Junsoo Im, Paul Brunnbauer, Umber Saleem, Muhammed Ikbal Sönmez, Carl Schulz, Margaret Nandudu, Joris Winters, Cristina E Molina, Johannes Petersen, Monika Stoll, Ulrich Schotten, Arne Hansen, Thomas Eschenhagen, Jussi T Koivumäki, Torsten Christ
Affiliations
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Cardiovascular Surgery, University Heart and Vascular Center, Hamburg, Germany.
- Division of Genetic Epidemiology, Institute of Human Genetics, University of Muenster, Münster, Germany.
- Department of Biochemistry, CARIM School for Cardiovascular Sciences, Maastricht University, Maastricht, The Netherlands.
Abstract
BACKGROUND AND PURPOSE
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have gained interest as a pharmacological model but their immaturity leads to uncertainty regarding translation. We studied the key player in maintaining ionic homeostasis, the Na +/K +-ATPase (NKA), in hiPSC-CM.
EXPERIMENTAL APPROACH
Atrial and ventricular engineered heart tissues (EHTs) were produced from hiPSC-CMs. For comparison, adult atrial and ventricular tissues were obtained from patients undergoing open heart surgery. We measured NKA gene expression, NKA pump currents (I NKA) and ouabain effects on action potentials and contractility. Computational modelling was used to further investigate the direct and indirect impacts of NKA inhibition.
KEY RESULTS
The mRNA abundance of the major NKA isoforms was higher in ventricular than atrial cardiomyocytes (adult and hiPSC-CM). Consistently, I NKA was also higher in ventricular than in atrial hiPSC-CM and higher in ventricular than in atrial adult cardiomyocytes. Ouabain potency to block I NKA did not differ between hiPSC-derived and adult cardiomyocytes. Ouabain shortened plateau phase in EHT and adult tissue. However, lower ouabain concentrations depolarized diastolic potential and depressed force more in EHTs, demonstrating a higher integrated sensitivity to NKA inhibition. Computational modelling indicated that weaker I K1 increases the susceptibility to depolarisation by NKA block.
CONCLUSIONS AND IMPLICATIONS
HiPSC-EHTs express NKA with biophysical characteristics and ouabain-sensitivity that are not different from human tissue. Action potential duration responses in EHT reproduces chamber-specific response pattern as seen in human heart. The higher sensitivity of EHTs to depolarize under ouabain-induced block of NKA needs to be considered when employing hiPSC-CM in drug research.
MeSH
Cells, Electrophysiology, Microscopy, Electron, Scanning Transmission, Pluripotent Stem Cells, Heart, Action Potentials, Stem Cells, Drug Therapy, Pharmacology, Induced Pluripotent Stem Cells, Tissues, Ouabain, Myocytes, Cardiac