Abstract
Cadmium, a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health. The molecular mechanisms of the cadmium-induced cardiotoxicity (CIC) have not been studied in human cardiomyocytes at the cellular level. Here we showed that human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) can recapitulate the CIC at the cellular level. The cadmium-treated hPSC-CMs exhibited cellular phenotype including reduced cell viability, increased apoptosis, cardiac sarcomeric disorganization, elevated reactive oxygen species, altered action potential profile and cardiac arrhythmias. RNA-sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium-treated hPSC-CMs, and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype. We further identified that suppression of PI3K/Akt signalling pathway is sufficient to reverse the CIC phenotype, which may play an important role in CIC. Taken together, our data indicate that hPSC-CMs can serve as a suitable model for the exploration of molecular mechanisms underlying CIC and for the discovery of CIC cardioprotective drugs.
Keywords:
MAPK; PI3K/Akt; apoptosis; cadmium-induced cardiotoxicity; electrophysiology; hPSC-CMs.
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cadmium Chloride / antagonists & inhibitors
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Cadmium Chloride / toxicity*
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Cardiotoxicity / genetics
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Cardiotoxicity / metabolism
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Cardiotoxicity / prevention & control
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Cell Differentiation / drug effects
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Cell Line
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Chromones / pharmacology
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Dose-Response Relationship, Drug
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation / drug effects*
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Humans
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Imides / pharmacology
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Insulin / pharmacology
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Models, Biological*
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Morpholines / pharmacology
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / metabolism
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Oxidative Stress / drug effects
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Phenotype
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / drug effects
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Pluripotent Stem Cells / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Quinolines / pharmacology
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Chir 99021
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Chromones
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IWR-1 compound
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Imides
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Insulin
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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Pyrimidines
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Quinolines
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Reactive Oxygen Species
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Cadmium Chloride