S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.
S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.
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S-双氯芬酸通过改善心脏间隙连接重塑来预防阿霉素诱导的小鼠心肌病
DOI：
10.1371/journal.pone.0026441
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Zhang H;Zhang A;Guo C;Shi C;Zhang Y;Liu Q;Sparatore A;Wang C
硫化氢（H2S）作为一种新型的气体介质，在哺乳动物心血管组织中发挥着重要作用。在本研究中，我们研究了S-双氯芬酸（2-[（2，6-二氯苯基）氨基]苯乙酸4-（3 H-1，2，二硫醇-3-庚-5-基）苯酯），一种新的双氯芬酸的H2S释放衍生物，在多柔比星诱导的心肌病小鼠模型中的心脏保护作用。在单剂量注射多柔比星（15 mg/kg，i. p.）后，雄性C57 BL/6 J小鼠每天给予S-双氯芬酸（25和50 µmol/kg，i. p.），双氯芬酸（25和50 µmol/kg，i. p.），NaHS（50 µmol/kg，i.p.），或相同体积的车辆。14天后观察S-双氯芬酸的心脏保护作用。结果表明，S-双氯芬酸（而非双氯芬酸）剂量依赖性地抑制阿霉素诱导的心脏间隙连接蛋白（连接蛋白43和连接蛋白45）下调，从而逆转心脏间隙连接的重塑。它也剂量依赖性地抑制阿霉素诱导的JNK激活的心脏。此外，S-双氯芬酸在该模型中产生剂量依赖性抗炎和抗氧化作用。因此，S-双氯芬酸显著减轻了阿霉素相关的心脏损伤和心功能不全，并提高了阿霉素诱导的心肌病小鼠的存活率。S-双氯芬酸的这些作用在很大程度上被NaHS模仿。因此，我们认为S-双氯芬酸体内释放的H2S有助于对阿霉素诱导的心肌病的保护作用。这些数据也提供了证据H2S在阿霉素诱导的心肌病的发病机制中的关键作用。
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.
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影响因子：
2.9
作者：
LABARCA, C;PAIGEN, K
通讯作者：
PAIGEN, K
影响因子：
7.3
作者：
Rossoni, G.;Sparatore, A.;Berti, F.
通讯作者：
Berti, F.
影响因子：
2.4
作者：
Desplantez, Thomas;Dupont, Emmanuel;Weingart, Robert
通讯作者：
Weingart, Robert
影响因子：
4.8
作者：
Kimura, Y;Kimura, H
通讯作者：
Kimura, H
影响因子：
37.8
作者：
Huang C;Zhang X;Ramil JM;Rikka S;Kim L;Lee Y;Gude NA;Thistlethwaite PA;Sussman MA;Gottlieb RA;Gustafsson AB
通讯作者：
Gustafsson AB