chir-99021 and Cardiotoxicity

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.

Topics: Cadmium Chloride; Cardiotoxicity; Cell Differentiation; Cell Line; Chromones; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Imides; Insulin; MAP Kinase Kinase 4; Models, Biological; Morpholines; Myocytes, Cardiac; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenotype; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pluripotent Stem Cells; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Quinolines; Reactive Oxygen Species; Signal Transduction