Dataset Information

Cytotoxicity and Toxicoproteomic Analysis of Pioglitazone Exposure in Human-derived Cardiomyocytes

ABSTRACT: Pioglitazone (PGZ) is a peroxisome proliferator-activated receptor gamma agonist widely used as an insulin sensitiser agent for type II diabetes mellitus. The heterogeneity of PGZ effects on cardiac tissue has remained controversial, as contradictory data exist in the literature. Nevertheless, a consensus has reported an associated increased risk of heart failure (HF) following chronic systemic exposure to PGZ, which has hampered its clinical use in diabetes management. The mechanism of PGZ-induced HF remains largely uncharacterised. Here, we report a comprehensive in vitro study combining a novel toxico-proteomic pipeline with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into PGZ cardiotoxicity and identify driver proteins associated with such effects. Cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production following PGZ exposure, suggesting that this decline underpins PGZ cardiotoxicity. Interestingly, proteomics analysis revealed that the mitochondrial dysfunction was attributed to PGZ mediating mitochondrial uncoupling and ultimately cardiomyocyte death. The type of cell death was also found to be related to the mitochondria—protein upregulation in the phosphoglycerate mutase family 5–dynamin-related protein 1 axis, suggesting mitochondrial-mediated necroptosis. Furthermore, our analysis 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 integrin-signalling pathways, responsible for PGZ-induced myocardial contractile failure. Collectively, our findings provide substantial mechanistic insight into PGZ adverse effects and may eventually provide the rationale for future optimisation of antidiabetic therapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cardiac Muscle Cell

DISEASE(S): Heart Failure

SUBMITTER: Abdullah AlSultan

LAB HEAD: Nicholas J. Rattray

PROVIDER: PXD048231 | Pride | 2025-05-06

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 22

Publications

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

Al Sultan Abdullah A Rattray Zahra Z Rattray Nicholas J W NJW

Metabolomics : Official journal of the Metabolomic Society 20241204 1

<h4>Introduction</h4>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.<h4>Objec ...[more]

PMID: 39636558

Similar Datasets

Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.

			Action	DRS
	Drug_1.raw	Raw
	Drug_10.raw	Raw
	Drug_2.raw	Raw
	Drug_3.raw	Raw
	Drug_4.raw	Raw