Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes DOI Creative Commons
Abdullah S. Sultan, Zahra Rattray, Nicholas J. W. Rattray

et al.

Journal of Applied Toxicology, Journal Year: 2024, Volume and Issue: 44(8), P. 1214 - 1235

Published: April 23, 2024

Abstract Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus their association with increased heart failure risk, limiting TZD use in management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive vitro investigation utilising novel toxicoproteomics pipeline coupled cytotoxicity assays human adult cardiomyocytes to elucidate mechanistic insights into cardiotoxicity. The assay findings showed significant loss of mitochondrial adenosine triphosphate production upon exposure either agents, which may underpin Our analysis revealed that dysfunction primarily stems from oxidative phosphorylation impairment, distinct signalling observed both agents. cell death differed strikingly between two rosiglitazone exhibiting features caspase‐dependent apoptosis implicating mitochondrial‐mediated necroptosis, as evidenced by protein upregulation phosphoglycerate mutase family 5–dynamin‐related 1 axis. Furthermore, our additional aspects cardiotoxicity, showcasing drug specificity. downregulation various proteins involved machinery processing endoplasmic reticulum was rosiglitazone‐treated cells, proteostasis Regarding pioglitazone, suggested potential activation interplay complement coagulation systems disruption cytoskeletal architecture, mediated through integrin‐signalling pathways responsible pioglitazone‐induced myocardial contractile failure. Collectively, this study unlocks substantial insight providing rationale future optimisation antidiabetic therapies.

Language: Английский

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes DOI Creative Commons
Abdullah S. Sultan, Zahra Rattray, Nicholas J. W. Rattray

et al.

Journal of Applied Toxicology, Journal Year: 2024, Volume and Issue: 44(8), P. 1214 - 1235

Published: April 23, 2024

Abstract Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus their association with increased heart failure risk, limiting TZD use in management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive vitro investigation utilising novel toxicoproteomics pipeline coupled cytotoxicity assays human adult cardiomyocytes to elucidate mechanistic insights into cardiotoxicity. The assay findings showed significant loss of mitochondrial adenosine triphosphate production upon exposure either agents, which may underpin Our analysis revealed that dysfunction primarily stems from oxidative phosphorylation impairment, distinct signalling observed both agents. cell death differed strikingly between two rosiglitazone exhibiting features caspase‐dependent apoptosis implicating mitochondrial‐mediated necroptosis, as evidenced by protein upregulation phosphoglycerate mutase family 5–dynamin‐related 1 axis. Furthermore, our additional aspects cardiotoxicity, showcasing drug specificity. downregulation various proteins involved machinery processing endoplasmic reticulum was rosiglitazone‐treated cells, proteostasis Regarding pioglitazone, suggested potential activation interplay complement coagulation systems disruption cytoskeletal architecture, mediated through integrin‐signalling pathways responsible pioglitazone‐induced myocardial contractile failure. Collectively, this study unlocks substantial insight providing rationale future optimisation antidiabetic therapies.

Language: Английский

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