Effects Of 5-fluorouracil On Myocardial Mitochondria Damage In Rats And Its Mechanism

Objective: To investigate the effects of different doses of 5-fluorouracil(5-FU)on myocardial mitochondrial function and ultrastructure,and to explore the possible mechanism of its damage.Methods: Thirty clean male SD rats were selected.There were randomly divided into three groups:the control group(normal saline),low dose of 5-fluorouracil(25mg/kg/d)group and high dose of 5-fluorouracil(50 mg/kg/d)group.After 5 days of continuous intraperitoneal injection,hungry for 24 hours after the last administration.The rats was anesthetized by 3% pentobarbital.Changes of cardiac structure and function in rats of each group were detected by small animal in vivo imaging and high resolution ultrasound instrument.The ultrastructural changes of cardiac myocytes in each group were examined by electron microscopy.To detect the content of ATP in myocardium with kit.Isolation of mitochondria by differential centrifugation and detection of mitochondrial membrane potential by probe JC-1.Detection of Mitochondrial fusion and fission protein expression in rat cardiac myocytes by western.Results:1.There was no significant change in cardiac structure and function by echocardiography in each group after different doses of 5-FU.2.Compared with the control group,the electron microscope of 5-FU low dose group showed myocardial aberration,sarcomere disorder,widening of perinuclear space and slight swelling of mitochondria.Crest partial rupture or disappearance.High dose group showed myocardial aberration,sarcomere disorder,widening of perinuclear space,slight swelling of mitochondria,partial rupture or disappearance of cristae,partial rupture of membrane,formation of matrix vacuoles.3.After different doses of 5-FU,the mitochondrial membrane potential decreased by 0.87 times and 0.75 times of that of the control group,respectively.The membrane potential of the high dose group decreased significantly(P < 0.05).The content of ATP in the myocardium was not significantly changed in the low dose group compared with the control group.Compared with the control group,the high dose group was significantly lower than that of the control group(P < 0.05).4.Compared with the control group,the expression of Mfn1 protein and Mfn2 protein were significantly decreased at the different dose of 5-FU,while the opa1 protein only decreased significantly at high dose(P < 0.05).However,the expression of mitochondrial mitotic related protein(drp1)and mitochondrial mitogenesis-related protein(fis1)were significantly increased at different doses of 5-FU(P < 0.01).Conclusions:1.In this experiment,5-fluorouracil had no obvious effect on the whole structure and function of rat heart,and different doses of 5-fluorouracil had obvious damage effect on mitochondria of rat cardiomyocytes.Mitochondria may be an early damage site of 5-fluorouracil toxicity of heart injury.2.The damage effect of 5-FU on mitochondria of rat cardiomyocytes is caused by excessive division and insufficient fusion of mitochondria,which results in the breakdown of the dynamic balance of mitochondria and the loss of function of mitochondria.