Abstract
The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX-related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX-induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose-dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX-related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX-related injury in Sirt1-deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX-related cardiac injury through activation of the Sirt1 signaling pathway.
Highlights
Doxorubicin (DOX) has been widely used to treat solid and haematopoietic tumours; a major limiting factor for the clinical use of DOX is irreversible cardiac toxicity
To knock down Sirt1 in cardiomyocytes, neonatal rat cardiac myocytes (NRCMs) were preincubated with siSirt1 (50 nmol/l) or siRNA (50 nmol/l) for 24 h and subjected to DOX treatment for 24 h. siSirt1 and scrambled siRNA were obtained from Invitrogen
We further investigated the inhibitory effect of jaceosidin on hydrogen peroxide and superoxide production in DOX-treated cells
Summary
Doxorubicin (DOX) has been widely used to treat solid and haematopoietic tumours; a major limiting factor for the clinical use of DOX is irreversible cardiac toxicity. DOX-induced cardiotoxicity is characterized by irreversible degenerative cardiomyopathy and congestive heart failure [1,2,3]. The pathogenesis of cardiotoxicity induced by DOX remains poorly understood, but accumulating evidence suggests the indispensable roles of free radical production and myocardial apoptosis [4]. It has been demonstrated that DOX-induced cardiotoxicity can be suppressed by the overexpression of superoxide dismutase (SOD) and catalase [8, 9]. These findings suggest that ROS production and myocardial apoptosis play important roles in DOX-induced cardiotoxicity. We speculated that the suppression of ROS production and apoptotic cell death might largely rescue DOXtriggered cardiotoxicity
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