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.
Highlights
Heart disease has a high mortality and morbidity worldwide
We found that the LPCs decreased significantly, which has been demonstrated to be accompanied by a decrease in ejection fraction when cardiovascular disease occurrs, and a decrease in Ejection fraction (EF) is associated with disorders in phospholipid metabolism (Marcinkiewicz-Siemion et al, 2018)
The combined analysis results showed that the occurrence of heart failure was mainly related to the metabolic disorders of fatty acid metabolism, glycolysis, TCA cycle, glycerophospholipid metabolism, glutathione metabolism, and amino acid metabolism
Summary
Heart disease has a high mortality and morbidity worldwide. Clinically, anthracyclines are a major reason of cardiotoxicity (Feijen et al, 2019). Doxorubicin (DOX) is an effective anticancer agent for the treatment of solid tumors and hematological malignancies, which can cause pathological and physiological damage to the heart, such as progressive cardiac dilation and systolic. Rochette et al showed in the study that DOX caused a significant reduction in left ventricular ejection fraction, leading to congestive HF (Rochette et al, 2015). In the treatment of breast cancer patients, HF is the main cause of death due to the use of anthracycline drugs, which can be manifested as, under the condition of no abnormal load, left ventricular dilation and poor function lead to cardiac systolic dysfunction (Zhang et al, 2020). Based on the above studies, when anthracycline is used as a chemotherapeutic agent, cardiac toxicity has become the main limiting factor, and the discovery, prevention, and treatment of it will be an important issue
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