Functional Impact of BeKm-1, a High-Affinity hERG Blocker, on Cardiomyocytes Derived from Human-Induced Pluripotent Stem Cells.
Stephan De WaardJérôme MontnachBarbara RibeiroSébastien NicolasVirginie ForestFlavien CharpentierMatteo Elia MangoniNathalie GaboritMichel RonjatGildas LoussouarnPatricia LemarchandMichel De WaardPublished in: International journal of molecular sciences (2020)
IKr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go-Related Gene (hERG, Kv11.1) potassium channels. The blockage of these channels by pharmacological compounds is associated to drug-induced long QT syndrome (LQTS), which is a life-threatening disorder characterized by ventricular arrhythmias and defects in cardiac repolarization that can be illustrated using cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs). This study was meant to assess the modification in hiPS-CMs excitability and contractile properties by BeKm-1, a natural scorpion venom peptide that selectively interacts with the extracellular face of hERG, by opposition to reference compounds that act onto the intracellular face. Using an automated patch-clamp system, we compared the affinity of BeKm-1 for hERG channels with some reference compounds. We fully assessed its effects on the electrophysiological, calcium handling, and beating properties of hiPS-CMs. By delaying cardiomyocyte repolarization, the peptide induces early afterdepolarizations and reduces spontaneous action potentials, calcium transients, and contraction frequencies, therefore recapitulating several of the critical phenotype features associated with arrhythmic risk in drug-induced LQTS. BeKm-1 exemplifies an interesting reference compound in the integrated hiPS-CMs cell model for all drugs that may block the hERG channel from the outer face. Being a peptide that is easily modifiable, it will serve as an ideal molecular platform for the design of new hERG modulators displaying additional functionalities.
Keyphrases
- induced pluripotent stem cells
- drug induced
- liver injury
- endothelial cells
- left ventricular
- magnetic resonance imaging
- smooth muscle
- high throughput
- dna methylation
- single cell
- computed tomography
- angiotensin ii
- high glucose
- skeletal muscle
- copy number
- magnetic resonance
- mass spectrometry
- mesenchymal stem cells
- reactive oxygen species
- bone marrow
- ionic liquid
- transcranial direct current stimulation
- image quality
- electronic health record
- angiotensin converting enzyme