Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. (14th February 2019)

• Record Type: Journal Article
• Authors: Rampoldi, Antonio; Singh, Monalisa; Wu, Qingling; Duan, Meixue; Jha, Rajneesh; Maxwell, Joshua T; Bradner, Joshua M; Zhang, Xiaoyu; Saraf, Anita; Miller, Gary W; Gibson, Greg; Brown, Lou Ann; Xu, Chunhui
• Is Part Of: Toxicological sciences. Volume 169:Number 1(2019)
• Page Start: 280
• Page End: 292
• Publication Date: 2019-02-14
• Subjects: cardiomyocytes -- calcium handling -- ethanol exposure -- induced pluripotent stem cells -- oxidative stress -- RNA-seq; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfz038
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Alcohol use prior to and during pregnancy remains a significant societal problem and can lead to developmental fetal abnormalities including compromised myocardia function and increased risk for heart disease later in life. Alcohol-induced cardiac toxicity has traditionally been studied in animal-based models. These models have limitations due to physiological differences from human cardiomyocytes (CMs) and are also not suitable for high-throughput screening. We hypothesized that human-induced pluripotent stem cell-derived CMs (hiPSC-CMs) could serve as a useful tool to study alcohol-induced cardiac defects and/or toxicity. In this study, hiPSC-CMs were treated with ethanol at doses corresponding to the clinically relevant levels of alcohol intoxication. hiPSC-CMs exposed to ethanol showed a dose-dependent increase in cellular damage and decrease in cell viability, corresponding to increased production of reactive oxygen species. Furthermore, ethanol exposure also generated dose-dependent increased irregular Ca 2+ transients and contractility in hiPSC-CMs. RNA-seq analysis showed significant alteration in genes belonging to the potassium voltage-gated channel family or solute carrier family, partially explaining the irregular Ca 2+ transients and contractility in ethanol-treated hiPSC-CMs. RNA-seq also showed significant upregulation in the expression of genes associated with collagen and extracellular matrix modeling, and downregulation of genes involved in cardiovascular system development and actin filament-based process. These results suggest that hiPSC-CMs can be a novel and physiologically relevant system for the study of alcohol-induced cardiac toxicity.