Taurine Has Potential Protective Effects Against The Chronic Cardiotoxicity Induced By Doxorubicin In Mice

Doxorubicin(DOX)is an anthracycline anti-tumor drug with a broad-spectrum anti-tumor effect and has the killing effect on tumor cells at different growth cycles.DOX has been clinically used to treat breast cancer,acute leukemia and lymphoma,etc.However,there are reports that DOX has the killing effect on tumor cells,also it has a strong affinity to myocardial tissue.Long-term accumulation of DOX will cause irreversible damage to the myocardium,eventually leading to arrhythmia and heart failure.Taurine is a cytoprotective free amino acid enriched in cardiomyocytes.It has been shown that intraperitoneal injection of taurine reduces acute myocardial injury resulted from by DOX,but there are few data about the effect of taurine on chronic myocardial injury induced by DOX.In this study,ICR mice were selected as experimental animals,long term DOX treatments by the intraperitoneal injection were used to simulate chronic myocardial injury similar to clinical medications,and taurine was supplemented by long-term drinking water to explore the protective effect of taurine on chronic DOX myocardial injury.The most important results include the following points:1.The expression of taurine synthase cysteine sulfonate decarboxylase(CSD)in mouse myocardium was detected by immunohistochemistry.The results showed that CSD was widely expressed in the cytoplasm of myocardium.The content of taurine in the myocardium of mice was detected by HPLC in the different group,the results showed that adding taurine in drinking water significantly increased the content of taurine in the myocardium of mice.In addition,Western Blot results showed that DOX increased the CSD level by 118.6%,while Taurine-DOX had no significant effect on CSD level compared with the controls.However,DOX treated alone did not significantly affect TauT expression,but it increased by 90.2%in taurine-DOX than the control.The above results indicated that myocardial cells have function to synthesize taurine by themselves,and exogenous taurine supplementation increased the taurine content in the myocardium,and DOX promoted the taurine synthesis in the myocardium,while Taurine-DOX treatment enhanced the taurine transportation.2.DOX treatment resulted in the decline in body weight,whereas the body weight in the Taurine-DOX mice did not have significant change throughout the duration of the experiment.The results demonstrated that taurine supplementation can restrain the weight loss caused by DOX.3.The activity of myocardial enzymes in the serum were assayed and the results showed that the enzyme activity of CK and LDH in the DOX-treated mice increased by 9.8%and 40.3%compared with the control group,which decreased by 8.2%and 18.0%respectively compared with DOX-treated mice,indicating that taurine reduced the myocardial damage caused by DOX.4.In order to further explore the toxic effect of DOX on myocardium,Superoxide dismutase(SOD),Reduced glutathione(GSH),Glutathione peroxidase 4(Gpx4)and Malondialdehyde(MDA)were assayed.The results showed that DOX decreased the SOD enzyme activity,the GSH content and the Gpx4 expression levels by 33.2%,37.0%and 28.5%respectively,thereby weakening the antioxidant capacity of the myocardium.In addition,the MDA content in the myocardium increased by 30.4%in DOX group,whereas taurine supplementation reduced the oxidative damage by decreasing MDA.5.The Connexin 43(Cx43)expression in the myocardium was detected by Western Blot and the results showed that the DOX treatment decreased the myocardium Cx43 expression,indicating that DOX decreased the gap junction protein,disrupted the dynamic balance and structural integrity of myocardium.However,Taurine-DOX treatment had no significant effect on myocardium Cx43 expression compared with the control group.6.The toxic effect of DOX on cardiomyocytes was examined by histological methods and it was observed that the cardiomyocytes were loosely arranged and the cell structure showed different degrees of damage after DOX treatment.In addition,it was observed that DOX caused the myocardial myofilament disorder,myofibril rupture and dissolution,mitochondrial edema,whereas Taurine-DOX treatment resulted in less myofilament dissolution and swollen mitochondria under the transmission electron microscopy.In addition,cleaved Caspase-3 and Bax/Bc12 were detected by Western blot and the results showed that DOX upregulated the levels of cleaved Caspase-3 and Bax/Bc12 by 98.4%and 67.2%respectively in myocardium,while taurine supplementation significantly down-regulated the levels of these apoptotic factors,indicating that taurine protected myocardium by reducing myocardial cell apoptosis.In summary,the results of the present study showed that DOX is myocardial cytotoxic,causing oxidative damage to cardiomyocytes,destroying the structure of cardiomyocytes,and enhancing cardiomyocyte apoptosis.Exogenous taurine supplementation can alleviate the toxicity of mouse cardiomyocytes caused by DOX.However,the related mechanisms need to be clarified in the further study.