Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue
Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks with the human equivalent dosage. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified, that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage. Overall design: After 8 weeks of oxaliplatin treatment, mice heart were collected and total RNA was extracted. There were 9 RNA samples, 4 from control and 5 from oxaliplatin group passed the integrity threshold (larger than 8) and were used for RNA sequencing. Differentially expressed genes between control and oxaliplatin-treated mice were identified with Partek software to study the effects of oxaliplatin on gene expression profile in mice heart.