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AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis.
Free Radic Biol Med. 2018 12; 129:59-72.FR

Abstract

Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.

Authors+Show Affiliations

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China.State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.Department of Cellular and Structural Biology, UT Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: reiter@uthscsa.edu.State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address: qiaoshubin@fuwaihospital.org.State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address: yuanjiansong@fuwaihospital.org.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30172748

Citation

Liu, Dong, et al. "AMPK/PGC1α Activation By Melatonin Attenuates Acute Doxorubicin Cardiotoxicity Via Alleviating Mitochondrial Oxidative Damage and Apoptosis." Free Radical Biology & Medicine, vol. 129, 2018, pp. 59-72.
Liu D, Ma Z, Di S, et al. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radic Biol Med. 2018;129:59-72.
Liu, D., Ma, Z., Di, S., Yang, Y., Yang, J., Xu, L., Reiter, R. J., Qiao, S., & Yuan, J. (2018). AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radical Biology & Medicine, 129, 59-72. https://doi.org/10.1016/j.freeradbiomed.2018.08.032
Liu D, et al. AMPK/PGC1α Activation By Melatonin Attenuates Acute Doxorubicin Cardiotoxicity Via Alleviating Mitochondrial Oxidative Damage and Apoptosis. Free Radic Biol Med. 2018;129:59-72. PubMed PMID: 30172748.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. AU - Liu,Dong, AU - Ma,Zhiqiang, AU - Di,Shouyin, AU - Yang,Yang, AU - Yang,Jingang, AU - Xu,Liqun, AU - Reiter,Russel J, AU - Qiao,Shubin, AU - Yuan,Jiansong, Y1 - 2018/08/30/ PY - 2018/07/04/received PY - 2018/08/22/revised PY - 2018/08/27/accepted PY - 2018/9/3/pubmed PY - 2019/10/1/medline PY - 2018/9/3/entrez KW - AMPK KW - Apoptosis KW - Cardiotoxicity KW - Doxorubicin KW - Melatonin KW - Mitochondria KW - PGC1α SP - 59 EP - 72 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 129 N2 - Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/30172748/AMPK/PGC1α_activation_by_melatonin_attenuates_acute_doxorubicin_cardiotoxicity_via_alleviating_mitochondrial_oxidative_damage_and_apoptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)31184-5 DB - PRIME DP - Unbound Medicine ER -