Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo
Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo
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DOI：
10.1038/bjp.2008.81
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发表时间：
2008-05-01
影响因子：
7.3
通讯作者：
Yang, B-F
中科院分区：
文献类型：
--
作者：
Zhao, X-Y;Li, G-Y;Yang, B-F
背景与目的：三氧化二砷（As（2）O（3））是一种强有力的抗氧化剂，但由于其严重的心脏毒性而限制了其临床应用。QT间期延长和细胞凋亡与As（2）O（3）的心脏毒性有关。本研究旨在探讨白藜芦醇对三氧化二砷（As（2）O（3））诱导的心肌细胞凋亡和心肌损伤的影响，实验方法：在小鼠体内建立三氧化二砷（As（2）O（3））诱导的心肌病模型，测定QT间期和血浆酶活性，并对心肌组织进行组织学检查和细胞凋亡评估。在H9 c2心肌细胞，活力，细胞凋亡，产生活性氧（ROS）和细胞的钙离子levels.Key结果：在小鼠模型中，白藜芦醇减少As（2）O（3）诱导的QT间期延长和心肌细胞损伤（细胞凋亡，肌原纤维损失和空泡化）。此外，增加乳酸脱氢酶的活性和谷胱甘肽过氧化物酶，过氧化氢酶和超氧化物歧化酶的活性下降，观察到在血浆中的As（2）O（3）处理的小鼠，这些变化被阻止预处理与白藜芦醇。吖啶橙子/溴化乙锭染色、TdT介导的dUTP缺口末端标记法和caspase-3活性检测显示，在As（2）O（3）处理的H9 c2心肌细胞中，白藜芦醇显著增加心肌细胞活力，减少细胞凋亡。As（2）O（3）诱导的H9 c2细胞ROS生成和细胞内钙动员也被resveratrol预处理所抑制。结论和意义：我们的研究结果表明，resveratrol显著减弱As（2）O（3）诱导的心脏QT间期延长、结构异常和氧化损伤。在H9 c2心肌细胞中，白藜芦醇也减少了As（2）O（3）处理诱导的细胞凋亡、ROS产生和细胞内钙动员。这些观察结果表明，白藜芦醇有可能防止心脏毒性的As（2）O（3）暴露患者。
Background and purpose: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury.Experimental approach: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured.Key results: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol.Conclusions and implications: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.