Functional and Transcriptional Characterization of Histone Deacetylase Inhibitor-Mediated Cardiac Adverse Effects in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Autor: Laure Cougnaud, Eddy Vlaminckx, An De Bondt, Hua Rong Lu, Ilse Van den Wyngaert, Ivan Kopljar, David J. Gallacher
Rok vydání: 2016
Předmět:
0301 basic medicine
Time Factors
Genotype
Heart Diseases
Transcription
Genetic
medicine.drug_class
Induced Pluripotent Stem Cells
Action Potentials
Pharmacology
Biology
Risk Assessment
Epigenesis
Genetic
03 medical and health sciences
chemistry.chemical_compound
Heart Rate
Panobinostat
medicine
Humans
Myocytes
Cardiac
Epigenetics
Induced pluripotent stem cell
Vorinostat
Cells
Cultured
Oligonucleotide Array Sequence Analysis
Cardiotoxicity
Dose-Response Relationship
Drug
Entinostat
Gene Expression Profiling
fungi
Histone deacetylase inhibitor
food and beverages
Arrhythmias
Cardiac
Cell Biology
General Medicine
Cell-Based Drug Development
Screening
and Toxicology
Myocardial Contraction
Histone Deacetylase Inhibitors
Phenotype
030104 developmental biology
Gene Expression Regulation
chemistry
Histone deacetylase
Developmental Biology
medicine.drug
Zdroj: Stem Cells Translational Medicine. 5:602-612
ISSN: 2157-6580
2157-6564
Popis: Histone deacetylase (HDAC) inhibitors possess therapeutic potential to reverse aberrant epigenetic changes associated with cancers, neurological diseases, and immune disorders. Unfortunately, clinical studies with some HDAC inhibitors displayed delayed cardiac adverse effects, such as atrial fibrillation and ventricular tachycardia. However, the underlying molecular mechanism(s) of HDAC inhibitor-mediated cardiotoxicity remains poorly understood and is difficult to detect in the early stages of preclinical drug development because of a delayed onset of effects. In the present study, we show for the first time in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) that HDAC inhibitors (dacinostat, panobinostat, vorinostat, entinostat, and tubastatin-a) induce delayed dose-related cardiac dysfunction at therapeutic concentrations associated with cardiac adverse effects in humans. HDAC inhibitor-mediated delayed effects on the beating properties of hiPS-CMs developed after 12 hours by decreasing the beat rate, shortening the field potential duration, and inducing arrhythmic behavior under form of sustained contractions and fibrillation-like patterns. Transcriptional changes that are common between the cardiotoxic HDAC inhibitors but different from noncardiotoxic treatments identified cardiac-specific genes and pathways related to structural and functional changes in cardiomyocytes. Combining the functional data with epigenetic changes in hiPS-CMs allowed us to identify molecular targets that might explain HDAC inhibitor-mediated cardiac adverse effects in humans. Therefore, hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and support identification of better HDAC inhibitors with an improved benefit-risk profile. Significance Histone deacetylase (HDAC) inhibitors are a promising class of drugs to treat certain cancers, autoimmune, and neurodegenerative diseases. However, treated patients can experience various cardiac adverse events such as hearth rhythm disorders. This study found that human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can predict cardiac adverse events in patients caused by HDAC inhibitors. Furthermore, transcriptional changes at the level of gene expression supported the effects on the beating properties of hiPS-CMs and highlight targets that might cause these cardiac adverse effects. hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and to support development of safer HDAC inhibitors.
Databáze: OpenAIRE
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