Protective effect of TBHQ against Doxorubicin-induced chronic cardiotoxicity in rats
Objective To investigate whether tertiary butylhydroquinone(TBHQ)exerts a protective effect against Doxorubicin(DOX)-induced chronic cardiotoxicity by modulating the nuclear factor E2-related factor(Nrf2)signaling pathway.Methods Thirty-two rats were randomly divided into four groups(n=8):control group(Con group),DOX group,TBHQ group,and DOX+TBHQ group.The rats were intraperitoneally injected with DOX(2.5 mg/kg)once a week for 6 weeks to construct the chronic cardiotoxicity model in DOX group and DOX+TBHQ group,while the rats were injected intraperitoneally with an equal volume of 0.9％NaCl once a week for 6 weeks in Con group and TBHQ group.The rats were given 25 mg/kg of TBHQ solution by gavage immediately after the administration of DOX from day 1,once a day for 6 weeks in TBHQ group and DOX+TBHQ group,while the rats were given an equal volume of ddH2O by gavage once a day for 6 consecutive weeks in Con group and DOX group.After the drug intervention,the structural and functional changes of heart were observed by cardiac ultrasound.The morphology and the fibrosis of heart tissue were observed by HE staining and Masson staining.Serum superoxide dismutase(SOD)and glycol propylene(MDA)levels were determined by the relevant kits,and serum interleukin-6(IL-6)and tumor necrosis factor-alpha(TNF-α)levels were detected by ELISA.The expressions of cardiac Nrf2 and heme oxygenase 1(HO-1)protein were detected by Western blot.Results Compared with Con group,the coordina-tion of ventricular wall motion was weakened in DOX group,the amplitude of motion was decreased,the left ventricular ejection fraction(LVEF)and the left ventricular short-axis shortening(LVFS)were decreased(P＜0.05),and the left ventricular end-diastolic internal diameter(LVEDD)and the left ventricular end-systolic internal diameter(LVESD)were increased(P＜0.05).Compared with DOX group,LVEDD,LVESD,LVEF and LVFS of rats were improved in DOX+TBHQ group(P＜0.05).HE staining and Masson staining showed that the myocardial injury condition and the myocardial fibrosis were improved,and the collagen volume fraction was decreased in rats in DOX+TBHQ group compared with DOX group(P＜0.05).Compared with Con group,the serum SOD activity was decreased in DOX group(P＜0.05),while the levels of MDA,TNF-α and IL-6 were increased(P＜0.05).Compared with DOX group,the serum SOD activity was increased in DOX+TBHQ group(P＜0.05),while the levels of TNF-α,IL-6 and MDA were decreased(P＜0.05).The expressions of Nrf2 and HO-1 proteins in heart tissue of rats in DOX group was decreased compared with Con group(P＜0.05),and the expressions of Nrf2 and HO-1 proteins in heart tissue of rats in DOX+TBHQ group was elevated compared with DOX group(P＜0.05).Conclusion TBHQ may play a protective role against DOX-induced chronic cardiotoxicity in rats by upregulating the Nrf2/HO-1 signaling pathway.
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