Protective Effects and Mechanism of Dimethyl Fumarate on Doxorubicin-Induced Cardiac Injury
Objective To investigate the protective effect of dimethyl fumarate(DMF)on doxorubicin(DOX)-induced cardiac injury in mice and its possible mechanism.Methods Eighteen male C57BL/6J mice were selected and randomly divided into control group,model group and treatment group,with 6mice in each group.In the model group,DOX(2.5mg/kg)was injected intraperitoneally for two weeks,once every three days,with a total of 15mg/kg;the control group was given equal proportion of normal saline.The experi-mental group was also treated with DOX for two weeks,and was given DMF(25mg/kg)once a day for consecutive seven days after the first week.The cardiac function of mice was monitored at0,3,7 and 14 days.The atrial natriuretic peptide(ANP)and brain natriuretic peptide(BNP)mRNA expression of myocardial were detected by real-time quantitative polymerase chain reaction(RT-qPCR),and plasma creatine kinase isoenzyme(CK-MB)and lactic acid dehydrogenase(LDH)levels were measured by ELISA(enzyme-linked immunosorbent assay).Hematoxylin-eosin(HE)staining was used to observe myocardial structure.Malondialdehyde(MDA),reduced glutathione(GSH),and oxidized glutathione(GSSG)content and superoxide dismutase(SOD)activity were measured;Western blot was used to detect the expression of nuclear factor erythroid-2-related factor 2(Nrf2),heme oxygenase-1(HO-1)and glutathione peroxidase 4(GPX4),a key protein of ferroptosis.Results In the model group,the heart function of mice continued to decline and reached the lowest level at 14days,left ventricular ejection fraction(LVEF)and left ventricular short-axis shortening rate(LVFS)were significantly lower than those in control group.Body weight and heart weight-to-tibia length ratio were lower than those of control group,while the mRNA expression of cardiac ANP and BNP was increased,the plasma CK-MB and LDH were increased,accompanied by cardiomyocyte edema,muscle fiber rupture and inflammatory infiltration.However,the cardiac dysfunction of mice in the treatment group was improved,and the myocardial damage and structural destruction were less severe.In addition,MDA and GSSG contents in the model group were significantly higher than those in the control group,GSH level and SOD activity were lower than those in the control group,and the expressions of Nrf2,HO-1 and GPx4 were decreased.Compared with the model group,the cardiac oxidative stress in the treatment group was improved,and the expressions of Nrf2,HO-1 and GPx4 were also up-regulated.Conclusion DMF inhibits fer-roptosis and alleviates DOX-induced cardiac oxidative stress through upregulation of Nrf2/HO-1/GPX4 pathway,thus improving cardi-ac damage.
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