Exploration the mechanism of doxorubicin-induced Heart failure in Rats by integration of proteomics and metabolomics data

Abstract

Background Heart failure is currently a worldwide systemic disease with high morbidity and mortality and is very common. At present, many studies have shown that heart failure is associated with obesity, hypertension and diabetes, but it is still unable to prevent the disease from progressing. Here, we elucidate the molecular mechanisms of doxorubicin–induced harmful effects on rat cardiac metabolism and function from a new perspective, using metabonomics and Proteomics analysis data. Methods The aim of this study was to use metabonomic and proteomic techniques to systematically elucidate the molecular mechanisms of doxorubicin (DOX)–induced heart failure (HF) in rat. In this study, we aimed to systematically elucidate the molecular action of Dox on rats heart and the reasons for DOX–induced the HF mechanism through the metabonomics tandem mass tag (TMT)–based quantitative proteomics approach. Rats were gavaged with DOX (3 mg/kg) for 6 weeks and the plasma metabonomics, cardiac tissue proteomics, histopathology and related proteins expression levels. Results A total of 278 proteins and 21 metabolites were significantly altered in rats following DOX treatments. The responsive proteins and metabolites were predominantly involved in Fatty acid metabolism, Glycolysis, glycerophospholipid metabolism, TCA cycle, Glutathione metabolism, Myocardial contraction. Conclusions The present study indicates the PTP1B 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, suggesting the PTP1B may serve as a potential target in the treatment of heart failure.

Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death

“…With the advent of techniques, comprehensive omics strategies come into vision and multi-omics analysis has been applied in DOX-associated cardiotoxicity for high-throughput data of every single cell, providing beneficial for diagnosis and therapy [105][106][107]. RNA-sequencing analysis (RNA-seq) and proteomics analysis were performed in hearts detecting thousands of genes or proteins and distinguished significantly differential expression groups (DEGs) [108][109][110][111].…”

“…Subsequent bioinformatics analysis given the fact the altered peptides were closely associated with mitochondrial function, energy generation, oxidationreduction process and oxidative phosphorylation [113]. Bioinformatics profiling of integrated multi-omics screened common pathways involved in DOX-induced cardiotoxicity, which is indicated to be associated with energy metabolism, amino acid metabolism, fatty acid metabolism, and enzyme activities [106,107]. However, the differences in experimental models, grouping methods, analysing approaches, and screening conditions lead to various database.…”

Investigation of the efficacy of tyrosol on doxorubicin-induced acute cardiotoxicity in rats

“…These decreases were thought to be due to tyrosol's antioxidant effect on heart tissue, which inhibits lipid peroxidation. Doxorubicin administration causes various histopathological changes, such as cardiomyocyte vacuolization in heart tissue, increased extracellular fibrosis, muscle fiber disorder, myofibril loss, enlarged and abnormally shaped mitochondria, inflammatory cell infiltration, increased cell death, cardiomyocyte apoptosis, edema of myocardial cells, myocardial tissue hemorrhage, blood vessel occlusion, pycnotic nuclei and necrosis (Kumrala et al 2015, Haybara et al 2019, Ma et al 2019, Öner et al 2019, Liao et al 2020, Sandamali et al 2020, Tiana et al 2020, Yuan et al 2020, Ahmed et al 2021, Wan et al 2021. When the heart tissue samples from the control and tyrosol groups were examined, the cardiac muscle cells were found to have normal histological features.…”

Systematic review of metabolomics approaches in identifying biomarkers of chemotherapy-induced cardiotoxicity among breast cancer patients

“…Lastly, this study found evidence of reduced beta-oxidation of fatty acids and enhanced oxidative stress with lower levels of superoxide dismutase in the myocardial tissue. Based on these, they suggested that the reduced energy production and reactive oxygen species accumulation led to dysfunctional myocardial contractility and HF [21].…”