Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell-derived cardiomyocytes

Area of Science:

• Environmental Toxicology
• Cardiovascular Research
• Stem Cell Biology

Background:

• Cadmium is a ubiquitous toxic heavy metal pollutant posing significant threats to human health.
• Molecular mechanisms of cadmium-induced cardiotoxicity (CIC) in human cardiomyocytes remain poorly understood at the cellular level.

Purpose of the Study:

• To establish and utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as a model to investigate CIC mechanisms.
• To identify key molecular pathways involved in cadmium-induced heart damage.

Main Methods:

• hPSC-CMs were treated with cadmium to induce cardiotoxicity.
• Cellular phenotypes including viability, apoptosis, sarcomeric structure, reactive oxygen species, action potentials, and arrhythmias were assessed.
• RNA-sequencing was performed to analyze differential gene expression and signaling pathways.
• Specific pathway inhibitors (P38 MAPK, ERK MAPK, JNK MAPK, PI3K/Akt) were used to determine their effects on CIC.

Main Results:

• Cadmium-treated hPSC-CMs displayed reduced viability, increased apoptosis, sarcomeric disorganization, elevated reactive oxygen species, altered action potentials, and cardiac arrhythmias.
• RNA-sequencing revealed a distinct transcriptome profile and activation of the MAPK signaling pathway.
• Suppression of P38 MAPK, but not ERK or JNK MAPK, rescued the CIC phenotype.
• Inhibition of the PI3K/Akt signaling pathway was sufficient to reverse CIC phenotypes.

Conclusions:

• hPSC-CMs effectively recapitulate cadmium-induced cardiotoxicity at the cellular level, serving as a valuable model.
• The P38 MAPK and PI3K/Akt signaling pathways are critical mediators of CIC.
• This model facilitates the exploration of CIC mechanisms and the discovery of cardioprotective drugs against cadmium toxicity.