Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Guo,Zhaohui; Yan,Miao; Chen,Lei; Fang,Pingfei; Li,Zhihua; Wan,Zimeng; Cao,Sisi; Hou,Zhenyan; Wei,Shanshan; Li,Wenqun; Zhang,Bikui

doi:10.3892/etm.2018.6614

Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Authors:
- Zhaohui Guo
- Miao Yan
- Lei Chen
- Pingfei Fang
- Zhihua Li
- Zimeng Wan
- Sisi Cao
- Zhenyan Hou
- Shanshan Wei
- Wenqun Li
- Bikui Zhang
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Affiliations: Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: August 17, 2018 https://doi.org/10.3892/etm.2018.6614
Pages: 3333-3344
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX‑induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3‑10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX‑injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase‑1, NAD(P)H dehydrogenase (quinone) 1, and glutamate‑cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA‑induced Nrf2 activation and reversed the effect of Tan IIA on the DOX‑induced inhibition of cell viability. These results suggest that the Nrf2‑dependent antioxidant response mediates the protective effect of Tan IIA on DOX‑induced cardiotoxicity.

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