Abstract
Hydrogen sulfide (H2S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H2S in the pathogenesis of doxorubicin-induced cardiomyopathy.
Highlights
Doxorubicin is an anthracycline antibiotic widely used in the treatment of a variety of human neoplastic diseases and solid cancers, but its clinical application is hampered by progressive and does-related cardiotoxicity including transient electrocardiographic abnormalities, cardiomyopathy and heart failure
In the present study, we examined the cardioprotective effect of S-diclofenac in a murine model of doxorubicin-induced cardiomyopathy and investigated the specific mechanisms of its effect
These results provide a solid basis for the use of H2S donor drugs in the treatment of doxorubicininduced cardiotoxicity
Summary
Doxorubicin is an anthracycline antibiotic widely used in the treatment of a variety of human neoplastic diseases and solid cancers, but its clinical application is hampered by progressive and does-related cardiotoxicity including transient electrocardiographic abnormalities, cardiomyopathy and heart failure. The efficacy of doxorubicin as a cytotoxic agent for the treatment of human tumors has prompted a search to develop new agents to reduce its cardiotoxicity [1,2,3,4,5]. CBS and CSE are widely distributed in tissues, CBS is the main H2Sforming enzyme in central nervous system while CSE is the major H2S-producing enzyme in cardiovascular system. Application of H2S donors may be a promising therapeutic strategy to prevent doxorubicin cardiotoxicity. Further studies are needed to develop novel and potent compounds that are capable of producing H2S slowly and stably
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