Sirtuin-3 (SIRT3) Protein Attenuates Doxorubicin-induced Oxidative Stress and Improves Mitochondrial Respiration in H9c2 Cardiomyocytes
Sirtuin-3 (SIRT3) Protein Attenuates Doxorubicin-induced Oxidative Stress and Improves Mitochondrial Respiration in H9c2 Cardiomyocytes
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DOI：
10.1074/jbc.m114.607960
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发表时间：
2015-04-24
影响因子：
4.8
通讯作者：
Dolinsky, Vernon W.
中科院分区：
文献类型：
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作者：
Cheung, Kyle G.;Cole, Laura K.;Dolinsky, Vernon W.
阿霉素 (DOX) 是一种化疗药物，可有效治疗多种癌症。然而，DOX引起的心脏功能障碍限制了其临床应用。 DOX 被认为对心肌细胞有害，因为它会干扰线粒体磷脂心磷脂并导致电子转移效率低下，从而导致活性氧 (ROS) 的产生。 Sirtuin-3 (SIRT3) 是一种 III 类赖氨酸脱乙酰酶，定位于线粒体，调节线粒体呼吸和氧化应激抵抗酶，例如超氧化物歧化酶-2 (SOD2)。本研究的目的是确定 SIRT3 是否可以阻止 DOX 诱导的线粒体 ROS 产生。给小鼠施用 DOX 可抑制心脏 SIRT3 表达，并且 DOX 诱导 H9c2 心肌细胞中 SIRT3 和 SOD2 表达呈剂量依赖性下降。与野生型细胞相比，SIRT3 缺失的小鼠胚胎成纤维细胞在 DOX 存在下产生显着更多的 ROS。野生型 SIRT3 的过表达增加了 DOX 处理的 H9c2 心肌细胞中的心磷脂水平，挽救了线粒体呼吸和 SOD2 表达，并减少了 DOX 处理后产生的 ROS 量。当 H9c2 细胞中表达脱乙酰酶缺陷的 SIRT3 时，这些效应就不存在。我们的结果表明，SIRT3 的过度表达会减弱 DOX 诱导的 ROS 产生，这可能涉及 SOD2 表达的增加和线粒体生物能的改善。 SIRT3 激活可能是治疗 DOX 引起的心脏功能障碍的潜在疗法。
Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electron transfer resulting in the production of reactive oxygen species (ROS). Sirtuin-3 (SIRT3) is a class III lysine deacetylase that is localized to the mitochondria and regulates mitochondrial respiration and oxidative stress resistance enzymes such as superoxide dismutase-2 (SOD2). The purpose of this study was to determine whether SIRT3 prevents DOX-induced mitochondrial ROS production. Administration of DOX to mice suppressed cardiac SIRT3 expression, and DOX induced a dose-dependent decrease in SIRT3 and SOD2 expression in H9c2 cardiomyocytes. SIRT3-null mouse embryonic fibroblasts produced significantly more ROS in the presence of DOX compared with wild-type cells. Overexpression of wildtype SIRT3 increased cardiolipin levels and rescued mitochondrial respiration and SOD2 expression in DOX-treated H9c2 cardiomyocytes and attenuated the amount of ROS produced following DOX treatment. These effects were absent when a deacetylase-deficient SIRT3 was expressed in H9c2 cells. Our results suggest that overexpression of SIRT3 attenuates DOX-induced ROS production, and this may involve increased SOD2 expression and improved mitochondrial bioenergetics. SIRT3 activation could be a potential therapy for DOX-induced cardiac dysfunction.