Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes

Al Sultan, Abdullah; Rattray, Zahra; Rattray, Nicholas J. W.

doi:10.1007/s11306-024-02097-z

Cited by 4 publications

(1 citation statement)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Extending upon our prior research employing toxicometabolomics approach in AC16 cells (Al Sultan et al, 2024), this study aimed to further assess the cardiotoxic effects of TZDs through comprehensively:…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes

Al Sultan,

Rattray,

Rattray

2024

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Introductionmentioning

confidence: 99%

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes

Al Sultan,

Rattray,

Rattray

2024

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

show abstract

Integrative analysis of toxicometabolomics and toxicoproteomics data: new molecular insights into thiazolidinedione-induced cardiotoxicity

Al Sultan,

Rattray,

Rattray

2024

Metabolomics

View full text Add to dashboard Cite

Introduction Despite the well-established efficacy of thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, in type II diabetes management, their potential contribution to heart failure risk remains a significant area of uncertainty. This incomplete understanding, which persists despite decades of clinical use of TZDs, has generated ongoing controversy and unanswered questions regarding their safety profiles, ultimately limiting their broader clinical application. Objective and methods This study presented a multi-omics approach, integrating toxicoproteomics and toxicometabolomics data with the goal of uncovering novel mechanistic insights into TZD cardiotoxicity and identifying molecular signatures predictive of side effect progression. Results Network analysis of proteo-metabolomic data revealed a distinct fingerprint of disrupted biochemical pathways, which were primarily related to energy metabolism. Downregulation of oxidative phosphorylation and fatty acid synthesis was coupled with increased activity in anaerobic glycolysis, the pentose phosphate pathway, and amino acid and purine metabolism. This suggests a potential metabolic shift in AC16 cells from fatty acid oxidation towards anaerobic glycolysis, potentially contributing to observed cardiotoxicity. Additionally, the study identified a marked disruption in the glutathione system, indicating an imbalanced redox state triggered by TZD exposure. Importantly, our analysis identified key molecular signatures across omics datasets, including prominent signatures of amino acids like L-ornithine, L-tyrosine and glutamine, which are evidently associated with heart failure, supporting their potential use for the early prediction of cardiotoxicity progression. Conclusion By uncovering a novel mechanistic explanation for TZD cardiotoxicity, this study simultaneously illuminates potential therapeutic interventions, opening avenues for future research to improve the safety profile of TZD agents. (250 words) Graphical abstracts

show abstract

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Sultan,

Rattray,

Rattray

2024

Preprint

Self Cite

View full text Add to dashboard Cite

Introduction Despite the well-established efficacy of thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, in type II diabetes management, their potential contribution to heart failure risk remains a significant area of uncertainty. This incomplete understanding, which persists despite decades of clinical use of TZDs, has generated ongoing controversy and unanswered questions regarding their safety profiles, ultimately limiting their broader clinical application. Objective and Methods This study presented a multi-omics approach, integrating toxicoproteomics and toxicometabolomics data with the goal of uncovering novel mechanistic insights into TZD cardiotoxicity and identifying molecular signatures predictive of side effect progression. Results Network analysis of proteo-metabolomic data revealed a distinct fingerprint of disrupted biochemical pathways, which were primarily related to energy metabolism. Downregulation of oxidative phosphorylation and fatty acid synthesis was coupled with increased activity in anaerobic glycolysis, the pentose phosphate pathway, and amino acid and purine metabolism. This suggests a potential metabolic shift in AC16 cells from fatty acid oxidation towards anaerobic glycolysis, potentially contributing to observed cardiotoxicity. Additionally, the study identified a marked disruption in the glutathione system, indicating an imbalanced redox state triggered by TZD exposure. Importantly, our analysis identified key molecular signatures across omics datasets, including prominent signatures of amino acids like L-ornithine, L-tyrosine and glutamine, which are established heart failure biomarkers, supporting their potential use for the early prediction of cardiotoxicity progression. Conclusion By uncovering a novel mechanistic explanation for TZD cardiotoxicity, this study simultaneously illuminates potential therapeutic interventions, opening avenues for future research to improve the safety profile of TZD agents.

show abstract

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes

Cited by 4 publications

References 31 publications

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human‐derived cardiomyocytes

Integrative analysis of toxicometabolomics and toxicoproteomics data: new molecular insights into thiazolidinedione-induced cardiotoxicity

Integrative Analysis of Toxicometabolomics and Toxicoproteomics Data: New Molecular Insights into Thiazolidinedione-Induced Cardiotoxicity

Contact Info

Product

Resources

About