Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell-derived cardiomyocytes.
Jiaxi ShenXiaochen WangDanni ZhouTongyu LiLing TangTingyu GongJun SuPing LiangPublished in: Journal of cellular and molecular medicine (2018)
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.
Keyphrases
- pi k akt
- signaling pathway
- heavy metals
- endothelial cells
- high glucose
- human health
- risk assessment
- cell cycle arrest
- oxidative stress
- single cell
- cell proliferation
- reactive oxygen species
- health risk assessment
- diabetic rats
- cell death
- pluripotent stem cells
- induced pluripotent stem cells
- left ventricular
- induced apoptosis
- gene expression
- drug induced
- climate change
- small molecule
- heart failure
- health risk
- genome wide
- rna seq
- high throughput
- electronic health record
- machine learning
- hypertrophic cardiomyopathy
- single molecule
- life cycle