Exploration the Mechanism of Doxorubicin-Induced Heart Failure in Rats by Integration of Proteomics and Metabolomics Data

Abstract

Heart failure is a common systemic disease with high morbidity and mortality worldwide. Doxorubicin (DOX) is a commonly used anthracycline broad-spectrum antitumor antibiotic with strong antitumor effect and definite curative effect. However, cardiotoxicity is the adverse reaction of drug dose cumulative toxicity, but the mechanism is still unclear. In this study, proteomics and metabonomics techniques were used to analyze the tissue and plasma of DOX-induced heart failure (HF) in rats and to clarify the molecular mechanism of the harmful effects of DOX on cardiac metabolism and function in rats from a new point of view. The results showed that a total of 278 proteins with significant changes were identified by quantitative proteomic analysis, of which 118 proteins were significantly upregulated and 160 proteins were significantly downregulated in myocardial tissue. In the metabonomic analysis, 21 biomarkers such as L-octanoylcarnitine, alpha-ketoglutarate, glutamine, creatine, and sphingosine were detected. Correlation analysis showed that DOX-induced HF mainly affected phenylalanine, tyrosine, and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, phenylalanine metabolism, biosynthesis of unsaturated fatty acids, and other metabolic pathways, suggesting abnormal amino acid metabolism, fatty acid metabolism, and glycerol phospholipid metabolism. It is worth noting that we have found the key upstream target of DOX-induced HF, PTP1B, which inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc, and AK4 proteins lead to oxidative stress. Therefore, we think that PTP1B may play an important role in the development of heart failure induced by doxorubicin and can be used as a potential target for the treatment of heart failure.

Investigation into potential mechanisms of metabolic syndrome by integrative analysis of metabolomics and proteomics

“…Protein identifications were performed using the MASCOT search engine (version 2.3.2; Matrix Science, London, UK) embedded into Proteome Discoverer 1.4 (Thermo Electron, San Jose, CA, USA) [ 15 ] (Suplementary information). The LC/MS raw data were searched in the UniProt-reviewed rat protein database and differentially expressed proteins were screened by the criteria of up-regulation greater than 1.2 times or down-regulation less than 0.833 and T-test P value less than 0.05 [ 3 ]. The statistical analysis of related data was performed using SPSS software 20.0.…”

“…Although the roles of the two main causes in MetS are plausible, its specific pathogenesis still remains unknown and it also lacks screening and optimal treatment for this disease. Currently, proteomics and metabonomics have been promising technologies for elucidating the mechanisms of diseases, which detect and identify various molecules at the levels of proteins and metabolites, and study their functions and interrelationships among various molecules [ 3 , 4 ]. Yu Yuan et al combined the two techniques to explore the mechanism of doxorubicin-induced heart failure in rats and found that PTP1B can be used as a potential target for the treatment of heart failure [ 3 ].…”

“…Currently, proteomics and metabonomics have been promising technologies for elucidating the mechanisms of diseases, which detect and identify various molecules at the levels of proteins and metabolites, and study their functions and interrelationships among various molecules [ 3 , 4 ]. Yu Yuan et al combined the two techniques to explore the mechanism of doxorubicin-induced heart failure in rats and found that PTP1B can be used as a potential target for the treatment of heart failure [ 3 ]. In recent years, some metabonomics studies have been used to detect changing levels of serum metabolites of MetS.…”

Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay

“…In metabolomic studies conducted on rats, disorders with energy metabolism, fatty acids oxidation, amino acids, purine and choline metabolism, and gut microbiota-related metabolism were all associated with DOX administration [50]. Treated rats display a reduction in crucial mitochondrial elements, including superoxide dismutase (SOD) and nuclear respiratory factor 2 (NRF-2), which mediate stress response, and protein tyrosine phosphatase 1B (PTP1B), whose activation impairs insulin receptor substrate 1 (IRS-1), leading to disorders of fatty acid metabolism and glycolysis [51]. Aldose reductase promotes high glucose-induced superoxide overproduction insult.…”

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

“…Doxorubicin has been hypothesised to directly affect cardiac substrate usage. In particular, radiotracer and metabolomics studies in rats have suggested a decrease in both glucose and fatty acid utilisation preceding the onset of cardiac functional decline [ 26 , 27 ]. Some rat studies have suggested doxorubicin inhibits fatty acid oxidation by preventing mitochondrial entry of long-chain fatty acids through direct inhibition of carnitine palmitoyltransferase I (CPT I) [ 28 ], whilst others have suggested this to be due to transcriptional alterations in the fatty acid oxidation pathway within mitochondria [ 29 ].…”