title: S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.
abstract: Hydrogen sulfide (H(2)S), 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 H(2)S-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 H(2)S 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 H(2)S in the pathogenesis of doxorubicin-induced cardiomyopathy.
authors: Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. huili.zhang815@gmail.com
authors: Huili
authors: H
authors: Zhang
authors: Alian
authors: A
authors: Zhang
authors: Changfa
authors: C
authors: Guo
authors: Chunzhi
authors: C
authors: Shi
authors: Yang
authors: Y
authors: Zhang
authors: Qing
authors: Q
authors: Liu
authors: Anna
authors: A
authors: Sparatore
authors: Changqian
authors: C
authors: Wang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D004317:Doxorubicin / Q000009:adverse effects*; D017629:Gap Junctions / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D013871:Thiones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C520611:2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester; D000903:Antibiotics, Antineoplastic; D013871:Thiones; D004008:Diclofenac; D004317:Doxorubicin