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

Author:

Sultan Abdullah Al1,Rattray Zahra1,Rattray Nicholas J. W.1

Affiliation:

1. University of Strathclyde

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

Reference39 articles.

1. Administration, U. F., & a., D. (2010). FDA Drug Safety Communication: Ongoing review of Avandia (rosiglitazone) and cardiovascular safety.

2. Administration, U. F., & a., D. (2012). FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. June 15, 2011.

3. Ahn, J. H., Seo, H., Park, W., Seok, J., Lee, J. A., Kim, W. J., Kim, G. B., Kim, K. J., & Lee, S. Y. (2020). Enhanced succinic acid production by Mannheimia employing optimal malate dehydrogenase. Nature communications, 11(1), 1970.

4. Al Sultan, A., Rattray, Z., & Rattray, N. J. (2023). Cytotoxicity and Toxicoproteomic Analysis of Pioglitazone Exposure in Human-derived Cardiomyocytes.

5. Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes;Al Sultan A;Metabolomics,2024

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