s-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodelings-diclofenac防止doxorubicin-induced心肌病小鼠通过改善心肌缝隙连接重构.pdfVIP

S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling 1 1 2 1 1 1 3 Huili Zhang *, Alian Zhang , Changfa Guo , Chunzhi Shi , Yang Zhang , Qing Liu , Anna Sparatore , Changqian Wang1* 1 Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China, 2 Department of Cardiac Surgery, ` Zhongshan Hospital, Fudan University, Shanghai, China, 3 Dipartimento di Scienze Farmaceutiche ‘‘Pietro Pratesi,’’ Universita degli Studi di Milano, Milano, Italy Abstract Hydrogen sulfide (H S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the 2 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 mmol/kg, i.p.), diclofenac (25 and 50 mmol/kg, i.p.), NaHS (50 mmol/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 hear