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: Huili Zhang, Alian Zhang, Changfa Guo, Chunzhi Shi, Yang Zhang, Qing Liu, Anna Sparatore, Changqian Wang
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e26441 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22039489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester
• Antibiotics, Antineoplastic
• Thiones
• Diclofenac
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (adverse effects)
• Cardiomyopathies (chemically induced, physiopathology, prevention & control)
• Diclofenac (analogs & derivatives, pharmacology, therapeutic use)
• Down-Regulation
• Doxorubicin (adverse effects)
• Gap Junctions (drug effects)
• Heart (drug effects, physiopathology)
• Mice
• Oxidative Stress (drug effects)
• Thiones (pharmacology, therapeutic use)