Abstract
BackgroundDoxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators.MethodsMale ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection.ResultsA cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement.ConclusionsSMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.
Highlights
Doxorubicin (DOX) is a chemotherapy drug for malignant tumors
Shenmai injection (SMI), at a dose of 5 g/kg by pretreatment, could significantly improve the body weight lost by DOX (P < 0.05)
Ascites was present in the DOX, DOX + SMI (L), DOX + SMI (M), and DOX + Aft – SMI (H) groups but not in the control, SMI (H), and DOX + SMI (H) groups
Summary
The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. We investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators. Doxorubicin (DOX), an anthraquinone antibiotic for cancer therapy, is widely used in clinic [1, 2]. DOX has severe cardiotoxic side effects, limiting its clinical application. Studies have shown that when the cumulative dose of DOX reaches more than 500 mg/m2, the risk of fatal cardiomyopathy increases. DOX leading to progressive and dose-related cardiotoxicity has been reported [3]. DOX-induced cardiomyopathy (DIC) has clinical features with poor prognosis and high mortality [4]. The use of DOX is another important cause of dilated cardiomyopathy that causes congestive heart failure
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