Patients treated with 5-fluorouracil (5-FU) can develop rare but potentially severe cardiac effects, including cardiomyopathy, angina pectoris, heart failure and cardiogenic shock. The specific pathologies and underlying mechanisms are yet to be fully understood. The results of previous studies have indicated that mitochondrial autophagy is widely detected in many angiocardiopathies. In the present study, the dynamic changes in the homeostasis of mitochondrial injury and autophagy were observed in rats treated with 5-FU for different durations. A corresponding control group and a 5-FU model group were established in groups of Sprague-Dawley rats aged 2 and 18 months, and the myocardial enzyme levels were determined at different time points. At 2 weeks post-model establishment, cardiac ultrasound and myocardial histological staining were performed, cardiomyocyte apoptosis and myocardial mitochondrial function were assessed, and mitochondrial ultrastructure was examined. In addition, the expression levels of autophagy-related proteins were evaluated in the 18-month-old rats on days 7 and 14 of 5-FU administration. The experimental results demonstrated that 5-FU induced an elevation in the levels of myocardial enzymes, as well as changes in the cardiac structure and function, and that these changes were more prominent over longer drug durations. In addition, 5-FU decreased the levels of myocardial mitochondrial ATP and mitochondrial membrane potential, and aggravated myocardial fibrosis and cardiomyocyte apoptosis compared with those observed in the untreated control group, treated with the same volume of saline as 5-FU in the 5-FU group. These injuries were particularly evident in aging rats. Notably, 5-FU increased the expression levels of myocardial mitochondrial autophagy-related proteins, and electron microscopy revealed a more severe autophagic state in the model groups compared with that in the control groups. In conclusion, 5-FU induced myocardial mitochondrial damage, the degree of which was more severe in aging rats compared with that in young rats. The mitochondrial autophagy induced by 5-FU was excessive, and the degree of autophagy was aggravated with increased 5-FU administration time.
Keywords: 5-fluorouocil; aging; cardiotoxicity; mitochondrial autophagy.
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