Dataset Information

Mouse heart toxicity - A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

ABSTRACT: Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cardiac Muscle Cell

DISEASE(S): Cardiomyopathy

SUBMITTER: Axel Ducret

LAB HEAD: Axel Ducret

PROVIDER: PXD001888 | Pride | 2017-01-03

REPOSITORIES: Pride

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Publications

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

O'Farrell Alice C AC Evans Rhys R Silvola Johanna M U JM Miller Ian S IS Conroy Emer E Hector Suzanne S Cary Maurice M Murray David W DW Jarzabek Monika A MA Maratha Ashwini A Alamanou Marina M Udupi Girish Mallya GM Shiels Liam L Pallaud Celine C Saraste Antti A Liljenbäck Heidi H Jauhiainen Matti M Oikonen Vesa V Ducret Axel A Cutler Paul P McAuliffe Fionnuala M FM Rousseau Jacques A JA Lecomte Roger R Gascon Suzanne S Arany Zoltan Z Ky Bonnie B Force Thomas T Knuuti Juhani J Gallagher William M WM Roivainen Anne A Byrne Annette T AT

PloS one 20170127 1

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated o ...[more]

PMID: 28129334

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Project description:Ethnopharmacological relevance: Shexiang Baoxin Pill (SBP) is a traditional formulation of a Chinese patent medicine, which has been commonly used for the treatment of cardiovascular disease (CVD) in China since the 1980s. Previous clinical studies have shown that SBP is safe and effective in patients with CVD, but the mechanism of the therapeutic effect is still poorly understood and requires further research. Aim of the study: This study aims to comprehensively understand the effects and the underlying mechanisms of SBP for CVD treatment by analyzing the whole proteome of myocardial infarction (MI) model rats with or without SBP treatment. Materials and methods: We evaluated the therapeutic effects of SBP on myocardial infarction model (MI) rats by performing the echocardiography analyses after 15-day treatment. And the label-free quantitative proteomic approach was utilized to investigate the whole proteome of the rat heart tissues from MI group (MI rats, n=3), SBP group (MI rats treated with SBP, n=3) and SOG group (sham operated rats, n=3) on the operation day (Day 0) and 15 days after operation (Day 15), respectively. The differentially expressed proteins were subsequently analyzed with bioinformatical methods such as KEGG pathway enrichment analysis, gene ontology (GO)-annotation analysis and protein-protein interaction (PPI) network analysis. Finally, the expression levels of two promising proteins were validated by immunoblotting. Results: The echocardiography analyses show SBP significantly improved the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) of MI rats. Additionally, 134 proteins were differentially expressed both between SBP/MI and SOG/MI, and 15 proteins were found closely related to CVD. The pathway enrichment and GO-annotation analysis of these differentially expressed proteins revealed that the proteins involved in cellular mitochondrial energy metabolism processes, such as fatty acid beta-oxidation and aerobic respiration, were significantly regulated under SBP treatments, of which fatty acid-binding protein 3 (FABP3) and myoglobin (MB) was significantly down-regulated in MI model group compared with SOG group and was returned to the basal level by SBP treatment. Expression levels of these two proteins were confirmed by immunoblotting experiments. Conclusions: These results we obtained in current study probably demonstrated that the cardio-protective effects of Shexiang Baoxin Pill might be achieved through the regulation of energy metabolism homeostasis in cardiac tissue.

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Dataset Information

Mouse heart toxicity - A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

Publications

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

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