Ophiopogonin D attenuates doxorubicin-induced autophagic cell death by relieving mitochondrial damage in vitro and in vivo.
It has been reported that ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from Ophiopogon japonicas, promotes antioxidative protection of the cardiovascular system. However, it is unknown whether OP-D exerts protective effects against doxorubicin (DOX)-induced autophagic cardiomyocyte injury. Here, we demonstrate that DOX induced excessive autophagy through the generation of reactive oxygen species (ROS) in H9c2 cells and in mouse hearts, which was indicated by a significant increase in the number of autophagic vacuoles, LC3-II/LC3-I ratio, and upregulation of the expression of GFP-LC3. Pretreatment with OP-D partially attenuated the above phenomena, similar to the effects of treatment with 3-methyladenine. In addition, OP-D treatment significantly relieved the disruption of the mitochondrial membrane potential by antioxidative effects through downregulating the expression of both phosphorylated c-Jun N-terminal kinase and extracellular signal-regulated kinase. The ability of OP-D to reduce the generation of ROS due to mitochondrial damage and, consequently, to inhibit autophagic activity partially accounts for its protective effects in the hearts against DOX-induced toxicity.
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Ying-Yu
YY
Zhang
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Chen
C
Meng
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Xin-Mu
XM
Zhang
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Cai-Hua
CH
Yuan
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Ming-Da
MD
Wen
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Zhong
Z
Chen
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Da-Chuan
DC
Dong
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Yan-Hong
YH
Gao
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z).
Chang
C
Liu
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China (Y.-Y.Z., C.M., C.-H.Y., M.-D.W., Z.C., D.-C.D., Y.-H.G., C.L., Z.Z.); Department of Clinical Medicine, Changchun Medical College, Changchun, China (Y.-Y.Z.); and Department of Biopharmaceutical, School of Pharmacy, Jilin University, Changchun, China (X.-M.Z) zhangzhao@njnu.edu.cn zhangzhaolab@163.com.
Zhao
Z
Zhang
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019610:Cytoprotection / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D013150:Spirostans / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D012503:Saponins; D013150:Spirostans; C046996:ophiopogonin D; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases