葡萄籽原花青素提取物对多柔比星致慢性心脏毒性的防治作用

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中图分类号：R541 文献标志码：A DOI：10.11958/20252608

Abstract： ObjectiveTo investigate the efect of grape seed proanthocyanidin extract （GSPE）on doxorubicin-induced chroniccardiotoxicitybyregulating thenuclearfactorE2-relatedfactor2（Nrf2）/hemeoxygenase-1（HO-1）signaling pathway. MethodsThirty-six 6-week-old SDrats were randomly divided into six groups n =6 for each group）： the control group （control）， the doxorubicin group（DOX），the doxorubicin+low-dose GSPE group（L-GSPE），the doxorubicin+medium-doseGSPE group （MGSPE），thedoxorubicin+high-doseGSPEgroup（H-GSPE）andthedoxorubicin+tert-butylhydroquinone group（TBHQ）.Except forthecontrolgroupratsinteothergroupswereijectedintraperitonallitdoxoubicin（2.5g/kg）oceweeklyfor6oseutive weeksto establishthe chroniccardiotoxicity model.Thecontrol groupreceived equal volume ofintraperitoneal injectionof 0.9% NaCl solution（1mL/kg）.Starting fromthefirstdayof doxorubicininjection，theL-GSPE，M-GSPEandH-GSPE groups were administered GSPE solutions atdoses of 100mg/kg 200mg/kg and 400mg/kg ， respectively， via oral gavage.The TBHQ group was given 25 mg/kg TBHQ solution， while the control group and the DOX group were given an equal volume of ddH 2′ O. Cardiac structure and function were evaluated using echocardiography.Cardiac tissue morphologyandfibrosis wereobserved via HEand Massontaining.Serumlevelsofuperoxidsmuase（SOD），alondialdehde（MDA），nterleukin-6（-6），umornecoiscto α （TNF- α ）， cardiac troponin T（cTnT）and brain natriuretic peptide （BNP） were measured using commercial kits and ELISA. Western blot assayandqRT-PCR were employed toassess proteinand mRNA expression levelsof Nif2，NAD（P）Hquinone oxidoreductase1（NQOl）and HO- incardiactissue.ResultsCompared withtheDOX group，thecardiac structureandfunction， myocardial injury and fibrosis were all improved in the GSPE-treated groups，serumlevels of TNF- α ，IL-6，MDA，cTnT and BNP decreased，andserumSODactivityproteinand mRNA expressionlevelsof Nrf2，HO-1and NQO1increased.Notably，the HGSPE group demonstrated more significant improvement compared to the L-GSPE group （ P<0.05 ）. Conclusion GSPE may exertpreventivendtherapeuticefectsagainstdoxorubicin-inducedchroniccardiotoxicitybyactivatingtheNrf2/HO-1sigaling pathway.

KeyWords： doxorubicin;cardiotoxicity; heme oxygenase-1; grape seed proanthocyanidin extract; Nrf2 signaling pathway

目前，心血管疾病和恶性肿瘤是严重影响人类生命健康的两大慢性疾病，随着治疗策略的不断更新，恶性肿瘤患者的预后和生存期极大改善，但与抗肿瘤治疗相关的不良心血管事件也在增多。（剩余11769字）