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.
Highlights
Cadmium (Cd), a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health and it ranks 8th on the Agency for Toxic Substances and Disease Registry List of Hazardous Substances (ATSDR, 2005).[1,2] Cd exposure by humans has dramatically increased, which are mainly through workplace, cigarette smoke, contaminated food and water.[3]
The mechanism by which cadmium causes the cardiotoxicity has not been studied in human cardiomyocytes at the cellular level
We show that, for the first time, hPSC-CMs can serve as a unique tool to model cadmium-induced cardiotoxicity in a dish, and this cell model recapitulates deleterious CIC phenotype
Summary
Cadmium (Cd), a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health and it ranks 8th on the Agency for Toxic Substances and Disease Registry List of Hazardous Substances (ATSDR, 2005).[1,2] Cd exposure by humans has dramatically increased, which are mainly through workplace, cigarette smoke, contaminated food and water.[3]. Cadmium-induced cardiotoxicity (CIC) has been studied mainly in cultured cardiomyocytes isolated from murine models.[24-30]. Human pluripotent stem cellderived cardiomyocytes (hPSC-CMs) offers a human-based, physiology-relevant and scalable cell source for disease modelling and drug screening.[31-35]. RNA-Sequencing (RNASeq) analyses revealed a differential transcriptome profile and activated MAPK signalling pathway in Cd-treated hPSC-CMs, and suppression of P38 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, it is the first in vitro stem cell model to study CIC, which provides a suitable model for the exploration of molecular mechanisms underlying CIC and for the discovery of CIC cardioprotective drugs
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